Oral liquid compositions including valsartan

ABSTRACT

An aspect of the present disclosure is directed to an oral liquid composition comprising valsartan with enhanced solubility and stability. Other aspects are directed to methods of using the oral liquid compositions for the treatment of hypertension, treatment of heart failure and reduction of cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation application claiming priority under35 U.S.C. § 120 to U.S. patent application Ser. No. 16/224,229, filedDec. 18, 2018, which application claims priority under 35 U.S.C. § 120as a continuation-in-part of co-pending U.S. patent application Ser. No.16/220,775, filed on Dec. 14, 2018. The entire disclosures of suchapplications are hereby incorporated herein by reference in theirentireties.

FIELD OF THE INVENTION

Provided herein are oral liquid compositions including valsartan withenhanced solubility. Also provided herein, are methods of using oralliquid compositions including valsartan for the treatment ofhypertension, treatment of heart failure and reduction of cardiovascularmortality in clinically stable patients with left ventricular failure orleft ventricular dysfunction following myocardial infarction.

BACKGROUND

Valsartan is a nonpeptide, orally active, and specific angiotensin IIreceptor blocker acting on the AT₁ receptor subtype. Angiotensin IIinteracts with specific receptors on the surface of a target cell. Ithas been possible to identify receptor subtypes which are termed, e.g.,AT₁- and AT₂-receptors. Significant efforts have been made to identifysubstances that bind to the AT₁-receptor. Such active ingredients areoften termed angiotensin II antagonists. Because of the inhibition ofthe AT₁-receptor, such antagonists can be used, e.g., asantihypertensives or for the treatment of congestive heart failure.Angiotensin II antagonists are therefore understood to be those activeingredients which bind to the AT₁-receptor subtype. Prolonged anduncontrolled hypertensive vascular disease ultimately leads to a varietyof pathological changes in target organs such as the heart and kidney.Sustained hypertension can lead an increased occurrence of stroke.

Valsartan is chemically described asN-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-L-valine.Valsartan is used for treating hypertension, treatment of heart failureand reduction of cardiovascular mortality in clinically stable patientswith left ventricular failure or left ventricular dysfunction followingmyocardial infarction.

Valsartan is typically administered as a solid oral dosage form such as,for example, tablets, pills, and capsules. Oral ingestion is the mostconvenient and commonly employed route of drug delivery due to its easeof administration, high patient compliance, cost effectiveness, reducedsterility constraints, and flexibility in the design of dosage form.

However, some patients, specifically pediatric and geriatric patientpopulations, may dislike or have difficulty swallowing solid oral dosageforms, which can lead to associated disadvantages, such as patientnon-compliance. In such situations, oral liquid dosage forms, includingsolutions, suspensions and emulsions, can be easier to administer andmore suitable for use.

Many marketed pharmaceutical products do not have regulatory approvalfor pediatric use, resulting in “off-label” prescribing by physicians.When a pharmaceutical product does not have a labeled indication forchildren, manufacturers do not produce strengths and dosage formsappropriate for the pediatric population. Extemporaneously-preparedformulations are a sub-optimal option in instances where commercialliquid formulations are not available. At present, liquid dosage formsfor valsartan are prepared by compounding tablets into a suspension.However, developing and compounding of pediatric formulations can bechallenging for dispensing pharmacists, resulting in a variety ofissues, including inaccurate dosing, poor stability, poor taste,adherence problems, and lack of standardizations in extemporaneouscompounding. Consumers requiring a liquid dosage form may be puttingthemselves at risk since the product may not be made consistently fromone pharmacist to another. Further, extemporaneously-prepared valsartanformulations have a short shelf life, typically a maximum shelf life ofonly 90 days.

Poor bioavailability of pharmaceuticals presents a major challenge indesigning oral dosage forms. The oral bioavailability depends on severalfactors, including aqueous solubility, drug permeability, dissolutionrate, first-pass metabolism, presystemic metabolism, and susceptibilityto efflux mechanisms. The most frequent causes of low oralbioavailability are attributed to poor solubility and low permeability.For orally administered drugs, solubility is the most important ratelimiting parameter to achieve their desired concentration in systemiccirculation for pharmacological response. Accordingly, liquidcompositions containing active pharmaceutical ingredients that arecompletely solubilized in a liquid composition are more advantageousover suspension compositions. The extent of solubility of a substance ina specific solvent is measured as the saturation concentration, at whichthe addition of more solute does not increase its concentration in thesolution. The extent of solubility ranges widely, from infinitelysoluble (fully miscible) (for example, ethanol in water) to poorlysoluble (for example, silver chloride in water). Solubility is based onthe highest-dose strength of an immediate release product. A drug isconsidered highly soluble when the highest dose strength is soluble in250 mL or less of aqueous media over the pH range of 1 to 7.5.

Accordingly, there remains a need for a highly bioavailable, highlysoluble, stable valsartan oral solution that can address these problems,while safely and effectively providing the proper and consistentadministration of valsartan with accuracy and precision to patients whohave difficulty swallowing solid dosage forms.

SUMMARY

Provided herein are stable oral liquid compositions including valsartan.In one aspect, the present disclosure provides an oral liquidcomposition comprising about 3.6 mg/mL to about 4.4 mg/mL valsartan, ora pharmaceutically acceptable salt or solvate thereof, whereinadministration of a 320 mg dose of the oral liquid composition to apatient provides an in vivo plasma profile having a valsartan AUC_(inf)between about 35,162 ng*hr/mL and about 72,130 ng*hr/mL is providedherein.

In another aspect, the present disclosure provides an oral liquidcomposition including about 3.6 mg/mL to about 4.4 mg/mL valsartan, or apharmaceutically acceptable salt or solvate thereof, whereinadministration of a dose of the oral liquid composition to a patientprovides an in vivo plasma profile with a valsartan AUC_(inf) within arange of about 114% to about 136% of the same dose from an oral tabletdosage form.

In another aspect, methods of administering an oral liquid compositionincluding about 3.6 mg/mL to about 4.4 mg/mL valsartan are provided,wherein the methods achieve a valsartan AUC_(inf) in the patient rangingfrom about 35,162 ng*hr/mL and about 72,130 ng*hr/mL.

In another aspect, oral liquid compositions comprising about 4 mg/mLvalsartan or a pharmaceutically acceptable salt or solvate thereof,about 2 mg/mL potassium sorbate, about 10 mg/mL sodium citrate, andwater are provided herein.

In some embodiments, the oral liquid compositions can further compriseabout 2 mg/mL methylparaben. In various embodiments, the oral liquidcompositions can further comprise about 0.2 mg/mL sucralose.

In some embodiments, the mole ratio of sodium citrate to valsartan isabout 3.7:1 in the oral liquid compositions. In certain embodiments, themole ratio of potassium sorbate to valsartan is about 1.5:1 in the oralliquid compositions. In various embodiments, the mole ratio of parabento valsartan is about 1.4:1 in the oral liquid compositions. In someembodiments, the oral liquid composition is substantially free ofsolids.

In some embodiments, the pH of the oral liquid composition is about 5.8to about 6.1. In certain embodiments, the sodium citrate can be orinclude sodium citrate dihydrate. In various embodiments, the pH of theoral liquid composition is about 6.0. In some embodiments, the totalimpurities in the oral liquid composition are not more than about 0.4%,by weight of the composition. In certain embodiments, the oral liquidcomposition is stable at a temperature ranging from about 20° C. toabout 35° C. and a relative humidity (“RH”) ranging from about 35% toabout 75% for up to about 24 months.

In another aspect, methods of treating hypertension comprisingadministering to a patient in need thereof an oral liquid compositioncomprising about 4 mg/mL valsartan or a pharmaceutically acceptable saltor solvate thereof, about 2 mg/mL potassium sorbate, about 10 mg/mLsodium citrate, and water are provided herein.

In yet another aspect, methods of treating heart failure comprisingadministering to a patient in need thereof an oral liquid compositioncomprising about 4 mg/mL valsartan or a pharmaceutically acceptable saltor solvate thereof, about 2 mg/mL potassium sorbate, about 10 mg/mLsodium citrate, and water are provided herein.

In another aspect, methods of reducing cardiovascular mortality inclinically stable patients with left ventricular failure or leftventricular dysfunction following myocardial infarction are providedherein, the methods comprising administering to a patient in needthereof an oral liquid composition comprising about 4 mg/mL valsartan ora pharmaceutically acceptable salt or solvate thereof, about 2 mg/mLpotassium sorbate, about 10 mg/mL sodium citrate, and water.

BRIEF DESCRIPTION OF THE DRAWINGS

Various features and characteristics of non-limiting and non-exhaustiveembodiments disclosed and described in this specification may be betterunderstood by reference to the accompanying figures, in which:

FIGS. 1A-1C are views of a 4 ounce glass container used to contain anoral liquid composition, as described herein, wherein FIG. 1A is anelevational view of the glass container, FIG. 1B is a plan view of abottom of the glass container of FIG. 1A, and FIG. 1C is a detail of athreaded neck of the glass container shown in FIGS. 1A and 1B.

FIGS. 2A and 2B are views of a container closure system that can be usedin conjunction with the container shown in FIGS. 1A-1C, wherein FIG. 2Ais an exterior elevational view of a ribbed, threaded closure cap andFIG. 2B is a sectional view of the cap shown in FIG. 2A.

FIGS. 3A-3C are views of a 16 ounce glass container used to contain anoral liquid composition, as described herein, wherein FIG. 3A is a frontelevational view of the glass container, FIG. 3B is a side elevationalview of the glass container of FIG. 3A, and FIG. 3C is a detail of athreaded neck of the glass container shown in FIGS. 3A and 3B.

FIGS. 4A and 4B are views of a container closure system that can be usedin conjunction with the container shown in FIGS. 3A-3C, wherein FIG. 4Ais an exterior elevational view of a ribbed, threaded closure cap andFIG. 4B is a sectional view of the cap shown in FIG. 4A.

FIG. 5 is a front elevational view of a 25 mL Unit Dose Cup made ofpolyethylene used to contain an oral liquid composition, as describedherein.

FIG. 6 is a linear plot of the valsartan mean plasma concentrationversus time post administration of an oral liquid composition includingvalsartan (4 mg/mL, a total of 320 mg valsartan) in healthy, adultsubjects under fed and fasting conditions.

FIG. 7 is a semi-log plot of the mean plasma valsartan concentrationversus time post administration of an oral liquid composition includingvalsartan (4 mg/mL, a total of 320 mg valsartan) in healthy, adultsubjects under fed and fasting conditions.

DETAILED DESCRIPTION

Provided herein are stable oral liquid compositions including valsartan.Such compositions can be useful in the treatment of hypertension,treatment of heart failure and reduction of cardiovascular mortality inclinically stable patients with left ventricular failure or leftventricular dysfunction following myocardial infarction. Thecompositions can provide advantages over conventional oral solid dosageadministration of valsartan including, for example, ease ofadministration, improved absorption, increased patient compliance, andaccurate/precise delivery of valsartan to the patient. Further,valsartan is fully solubilized in the oral liquid compositions,providing oral liquid compositions that have improved bioavailabilityover liquid compositions that are suspensions, in which valsartan is notfully solubilized.

As used herein the terms “suspension” and “suspensions” refer to liquidformulations in which the solute particles of a substance are suspendedwithin a solvent and thus remain undissolved in the formulation. Thedegree to which a substance dissolves in a solvent to result in asolution is known as solubility. Solubility is the property of a solid,liquid, or gaseous chemical substance called a solute to dissolve in asolid, liquid or gaseous solvent. The solubility of a substancefundamentally depends on the physical and chemical properties of thesolute and solvent, as well as on temperature, pressure, and presence ofother chemicals (including changes to the pH) of the solution. As usedherein, the phrase “fully solubilized” refers to the completesolubilization of a solute at a particular concentration in a solvent.

Certain segments of the population have difficulty ingesting andswallowing solid oral dosage forms. This often leads to non-compliancewith the recommended therapy with solid dosage forms and can result inless-than-effective therapy. Moreover, an increased risk of choking canoccur when children or the elderly take solid dosage forms.

Currently, a liquid alternative to solid oral dosage forms of valsartancan be prepared by a compounding pharmacist where valsartan solid dosageforms are mixed into a liquid. However, forming valsartan liquidcompositions using such techniques can have significant drawbacks,including forming suspensions rather than solutions, large variabilityin the actual dosage amount of valsartan, incomplete or inconsistentsuspension of the valsartan solid dosage form in the liquid, rapidinstability, inconsistent formulation methods per compoundingpharmacist, and several other potential issues.

It has now been discovered that an oral liquid valsartan compositionthat includes a citrate salt buffering agent and the sorbate salt andparaben preservatives, and having a pH of about 5.8 to about 6.1,surprisingly and unexpectedly provide markedly improved solubility ofvalsartan. For example, the inventors found that increasing the pH ofthe acidic valsartan composition from about 4 to about 6, increased thesolubility of valsartan by a factor of about 1000. Further, suchcompositions exhibit surprising and unexpected stability up to about 18months, or in some cases longer. In some embodiments, the oral liquidvalsartan compositions exhibit a stability of up to 24 months or more.

Embodiments provided herein provide safe and effective administration ofvalsartan for the treatment of hypertension, treatment of heart failure,and reduction of cardiovascular mortality in clinically stable patientswith left ventricular failure or left ventricular dysfunction followingmyocardial infarction.

As used herein, “valsartan” refers to any of valsartan base, its salt,solvate, derivative isomer or polymorph thereof. Suitable compoundsinclude the free base, organic and inorganic salts, isomers, isomersalts, solvates, polymorphs, amorphous forms, complexes, etc. Valsartancan be purchased from commercial sources or can be prepared according toknown methods such as, for example, methods described in U.S. Pat. No.5,399,578 (incorporated herein by reference in its entirety). In certainembodiments, the valsartan used in compositions disclosed herein is orincludes valsartan-free base. In various embodiments, the valsartan usedin compositions disclosed herein is or includes a valsartan salt. Insome embodiments, the valsartan used in compositions disclosed herein isor includes a solvate.

Oral Liquid Compositions Containing Valsartan:

In one aspect, certain oral liquid compositions comprise valsartan and acombination of citrate salt, sorbate salt, and a paraben are disclosed.The citrate salt is a buffering agent and the sorbate salt and parabenare preservatives, and they are present in the oral liquid compositionsin ratios and amounts to provide an unexpectedly highly solubilizedcomposition. Such oral liquid compositions also may be unexpectedlystable. In some embodiments, the oral liquid compositions aresubstantially free of solids, whereby all components are fullysolubilized. The phrase “substantially free of solids”, as used hereinrefers the characteristic wherein a solution is essentially orfundamentally devoid of solid particulates.

In some embodiments, valsartan is present in a concentration of about3.6 mg/mL to about 4.4 mg/mL of the oral liquid composition, or at anyvalue or in any range subsumed therein. In certain embodiments,valsartan is present in the oral liquid composition in a concentrationranging from about 3.0 mg/mL to about 5.0 mg/mL, about 3.2 mg/mL toabout 4.8 mg/mL, about 3.5 mg/mL to about 4.5 mg/mL, about 3.6 mg/mL toabout 4.4 mg/mL, about 3.7 mg/mL to about 4.3 mg/mL, about 3.9 mg/mL toabout 4.1 mg/mL, about 3.5 mg/mL to about 4.1 mg/mL, about 3.6 mg/mL toabout 4.1 mg/mL, about 3.7 mg/mL to about 4.1 mg/mL, about 3.8 mg/mL toabout 4.2 mg/mL, about 3.6 mg/mL to about 4.2 mg/mL, or about 3.7 mg/mLto about 4.3 mg/mL of the oral liquid composition. In variousembodiments, valsartan is present in a concentration of about 3.8 mg/mL,about 3.9 mg/mL, about 4 mg/mL, about 4.1 mg/mL, or about 4.2 mg/mL ofthe oral liquid composition. In certain embodiments, valsartan ispresent in a concentration of about 4.0 mg/mL of the oral liquidcomposition.

In some embodiments, valsartan is present in a concentration of fromabout 20% w/w to about 24% w/w of the total solids used to prepare theoral liquid composition, or at any concentration or within anyconcentration range subsumed therein. In certain embodiments, valsartanis present in a concentration of about 20.4% w/w to about 23.6% w/w ofthe total solids used to prepare the oral liquid composition. In variousembodiments, valsartan is present in a concentration, by weight (w/w) ofthe total solids used to prepare the oral liquid composition, rangingfrom about 15% to about 25%, about 16% to about 24.5%, about 17% toabout 24%, about 18% to about 223.9%, about 17% to about 23.9%, about18% to about 23.9%, about 19% to about 23.8%, about 20% to about 23.8%,about 20.1% to about 23.8%, about 20.2% to about 23.8%, about 20.3% toabout 23.7%, about 20.5% to about 23.7%, about 20.6% to about 23.6%,about 20.4% to about 23.5%, about 21.0% to about 23.0%, about 21.5% toabout 23.5%, or about 20.3% to about 23.6%. In certain embodiments,valsartan is present in a concentration, by weight (w/w), of about 20.0%w/w, about 20.1% w/w, about 20.2% w/w, about 20.3% w/w, about 20.4% w/w,about 20.5% w/w, about 20.6% w/w, about 20.7% w/w, about 20.8% w/w,about 20.9% w/w, about 21.0% w/w, about 21.1% w/w, about 21.2% w/w,about 21.3% w/w, about 21.4% w/w, about 21.5% w/w, about 21.6% w/w,about 21.7% w/w, about 21.8% w/w, about 21.9% w/w, about 22.0% w/w,about 22.1% w/w, about 22.2% w/w, about 22.3% w/w, about 22.4% w/w,about 22.5% w/w, about 22.6% w/w, about 22.7% w/w, about 22.8% w/w,about 22.9% w/w, about 23.0% w/w, about 23.1% w/w, about 23.2% w/w,about 23.3% w/w, about 23.4% w/w, about 23.5% w/w, about 23.6% w/w,about 23.7% w/w, about 23.8% w/w, about 23.9% w/w, or about 24.0% w/w ofthe total solids used to prepare the oral liquid composition.

In some embodiments, the oral liquid composition has a pH of about 5.8to about 6.2, or at any value or in any range subsumed therein. In otherembodiments, the oral liquid composition has a pH of about 5.9 to about6.1. In certain embodiments, the oral liquid composition has a pHranging from about 5.0 to about 7.0, about 5.1 to about 6.9, about 5.2to about 6.8, about 5.3 to about 6.7, about 5.4 to about 6.6, about 5.5to about 6.5, about 5.6 to about 6.4, about 5.7 to about 6.3, about 5.9to about 6.1. In various embodiments, the oral liquid composition has apH of about 5.8, about 5.9, about 6.0, about 6.1, or about 6.2.

In some embodiments of the oral liquid composition, the citrate salt isor includes a group IA or group 2A salt. In certain embodiments, thecitrate salt is or includes sodium citrate, potassium citrate, calciumcitrate, magnesium citrate, or hydrates, solvates or anhydrous formsthereof. In various embodiments, the citrate salt is or includes sodiumcitrate. In some embodiments, the citrate salt is or includes monosodiumcitrate, disodium citrate, trisodium citrate, trisodium citratedihydrate, anhydrous trisodium citrate, disodium hydrogen citrate,disodium citrate sesquihydrate, calcium citrate, or magnesium citrate.In some embodiments, the citrate salt is or includes sodium citratedihydrate.

In some embodiments, the citrate salt is present in the oral liquidcomposition in amounts sufficient to provide a pH of about 5.8 to about6.2, or at any value or in any range subsumed therein. In certainembodiments, the citrate salt is present in the oral liquid compositionin amounts sufficient to provide a pH of about 5.2 to about 6.8, about5.3 to about 6.7, about 5.4 to about 6.6, about 5.3 to about 6.5, about5.4 to about 6.4, about 5.5 to about 6.3, about 5.6 to about 6.3, about5.7 to about 6.2, or about 5.9 to about 6.1. In various embodiments, thecitrate salt is present in the oral liquid composition in an amountsufficient to provide a pH of about 5.8, about 5.9, about 6.0, about6.1, or about 6.2.

In some embodiments, sodium citrate is present in a concentration offrom about 9.8 mg/mL to about 10.2 mg/mL of the oral liquid composition,or in any concentration or within any concentration range subsumedtherein. In certain embodiments, sodium citrate is present in aconcentration of from about 9.3 mg/mL to about 10.7 mg/mL, about 9.4mg/mL to about 10.6 mg/mL, about 9.5 mg/mL to about 10.5 mg/mL, about9.6 mg/mL to about 10.4 mg/mL, about 9.7 mg/mL to about 10.3 mg/mL,about 9.9 mg/mL to about 10.2 mg/mL, about 9.8 mg/mL to about 10.3mg/mL, or about 9.9 mg/mL to about 10.1 mg/mL of the oral liquidcomposition. In various embodiments, sodium citrate is present in aconcentration of about 9.8 mg/mL, about 9.9 mg/mL, about 10.0 mg/mL,about 10.1 mg/mL, or about 10.2 mg/mL of the oral liquid composition. Insome embodiments, sodium citrate is present in a concentration of about10.0 mg/mL of the oral liquid composition.

In some embodiments, sodium citrate is present in a concentration offrom about 52% w/w to about 58% w/w of the total solids used to preparethe oral liquid composition, or in any concentration or within anyconcentration range subsumed therein. In other embodiments, sodiumcitrate is present a concentration of from about 52.6% w/w to about57.4% w/w of the total solids used to prepare the oral liquidcomposition. In various embodiments, sodium citrate is present in aconcentration of from about 48% to about 62%, about 49% to about 61%,about 50% to about 60%, about 51% to about 59%, about 52% to about 60%,about 52% to about 61%, about 50% to about 58%, about 51% to about 58%,about 52.1% to about 57.1%, about 52.2% to about 57.2%, about 52.3% toabout 57.6%, about 52.4% to about 57.5%, about 52.5% to about 57.7%, orabout 52.3% to about 57.5% w/w of the total solids used to prepare theoral liquid composition. In certain embodiments, sodium citrate ispresent in a concentration of about 52.0% w/w, about 52.1% w/w, about52.2% w/w, about 52.3% w/w, about 52.4% w/w, about 52.5% w/w, about52.6% w/w, about 52.7% w/w, about 52.8% w/w, about 52.9% w/w, about53.0% w/w, about 53.1% w/w, about 53.2% w/w, about 53.3% w/w, about53.4% w/w, about 53.5% w/w, about 53.6% w/w, about 53.7% w/w, about53.8% w/w, about 53.9% w/w, about 54.0% w/w, about 54.1% w/w, about54.2% w/w, about 54.3% w/w, about 54.4% w/w, about 54.5% w/w, about54.6% w/w, about 54.7% w/w, about 54.8% w/w, about 54.9% w/w, about55.0% w/w, about 55.1% w/w, about 55.2% w/w, about 55.3% w/w, about55.4% w/w, about 55.5% w/w, about 55.6% w/w, about 55.7% w/w, about55.8% w/w, about 55.9% w/w, about 56.0% w/w, about 56.1% w/w, about56.2% w/w, about 56.3% w/w, about 56.4% w/w, about 56.5% w/w, about56.6% w/w, about 56.7% w/w, about 56.8% w/w, about 56.9% w/w, about57.0% w/w, about 57.1% w/w, about 57.2% w/w, about 57.3% w/w, about57.4% w/w, about 57.5% w/w, about 57.6% w/w, about 57.7% w/w, about57.8% w/w, about 57.9% w/w, or about 58.0% w/w of the total solids usedto prepare the oral liquid composition.

In some embodiments of the oral liquid composition, the sorbate saltincorporated therein is or includes a group IA or a group IIA salt. Inother embodiments, the sorbate salt is or includes lithium sorbate,potassium sorbate, sodium sorbate, calcium sorbate, or magnesiumsorbate. In some embodiments, the sorbate salt is present in an amountsufficient to provide a stable composition, for example, providinganti-microbial activity that prevents growth and/or spread of bacteriaand molds. In some embodiments, the sorbate salt is present in aconcentration of from about 1 mg/mL to about 3 mg/mL of the oral liquidcomposition, or in any concentration or within any concentration rangesubsumed therein. In certain embodiments, the sorbate salt is present ina concentration of from about 0.8 mg/mL to about 3.2 mg/mL, about 0.9mg/mL to about 3.1 mg/mL, about 1.1 mg/mL to about 2.9 mg/mL, about 1.2mg/mL to about 2.8 mg/mL, about 1.3 mg/mL to about 2.7 mg/mL, about 1.4mg/mL to about 2.6 mg/mL, about 1.5 mg/mL to about 2.5 mg/mL, about 1.5mg/mL to about 2.4 mg/mL, about 1.6 mg/mL to about 2.3 mg/mL, about 1.7mg/mL to about 2.3 mg/mL, about 1.8 mg/mL to about 2.2 mg/mL, about 1.9mg/mL to about 2.1 mg/mL, about 1.6 mg/mL to about 2.2 mg/mL, or about1.8 mg/mL to about 2.5 mg/mL of the oral liquid composition.

In some embodiments, the sorbate salt is or includes potassium sorbate.In certain embodiments, potassium sorbate is present in a concentrationof from about 1.8 mg/mL to about 2.2 mg/mL of the oral liquidcomposition, or in any concentration or within any concentration rangesubsumed therein. In certain embodiments, the potassium sorbate ispresent in a concentration of from about 0.8 mg/mL to about 3.2 mg/mL,about 0.9 mg/mL to about 3.1 mg/mL, about 1.1 mg/mL to about 2.9 mg/mL,about 1.2 mg/mL to about 2.8 mg/mL, about 1.3 mg/mL to about 2.7 mg/mL,about 1.4 mg/mL to about 2.6 mg/mL, about 1.5 mg/mL to about 2.5 mg/mL,about 1.5 mg/mL to about 2.4 mg/mL, about 1.6 mg/mL to about 2.3 mg/mL,about 1.7 mg/mL to about 2.3 mg/mL, about 1.8 mg/mL to about 2.2 mg/mL,about 1.9 mg/mL to about 2.1 mg/mL, about 1.6 mg/mL to about 2.2 mg/mL,or about 1.8 mg/mL to about 2.5 mg/mL of the oral liquid composition. Invarious embodiments, potassium sorbate is present in a concentration ofabout 1.8 mg/mL, about 1.9 mg/mL, about 2.0 mg/mL, about 2.1 mg/mL, orabout 2.2 mg/mL of the oral liquid composition.

In some embodiments, the sorbate salt is present in a concentration offrom about 5% w/w to about 15% w/w of the total solids used to preparethe oral liquid composition, or in any concentration or within anyconcentration range subsumed therein. In certain embodiments, thesorbate salt is present in a concentration of from about 9% w/w to about13% w/w of the total solids used to prepare the oral liquid composition.In certain embodiments, the sorbate salt is present in a concentrationof from about 4% w/w to about 16% w/w, about 6% w/w to about 14% w/w,about 7% w/w to about 13% w/w, about 8% w/w to about 15% w/w, about 9%w/w to about 14% w/w, about 10.5% w/w to about 11.5% w/w, about 11% w/wto about 13% w/w, or about 10% w/w to about 13% w/w of the total solidsused to prepare the oral liquid composition. In various embodiments, thesorbate salt is present in a concentration of from about 10% w/w toabout 12% w/w of the total solids used to prepare the oral liquidcomposition.

In some embodiments, potassium sorbate is present in a concentration offrom about 9.5% w/w to about 12.5% w/w of the total solids used toprepare the oral liquid composition, or in any concentration or withinany concentration range subsumed therein. In certain embodiments,potassium sorbate is present in a concentration of from about 9.0% w/wto about 13% w/w, about 9.1% w/w to about 12.9% w/w, about 9.2% w/w toabout 12.8% w/w, about 9.3% w/w to about 12.7% w/w, about 9.4% w/w toabout 12.6% w/w, about 9.6% w/w to about 12.5% w/w, about 9.7% w/w toabout 12.4% w/w, about 9.8% w/w to about 12.4% w/w, about 9.9% w/w toabout 12.3% w/w, or about 10% w/w to about 13% w/w of the total solidsused to prepare the oral liquid composition. In some embodiments,potassium sorbate is present in a concentration of about 9.5% w/w, about9.6% w/w, about 9.7% w/w, about 9.8% w/w, about 9.9% w/w, about 10.0%w/w, about 10.1% w/w, about 10.2% w/w, about 10.3% w/w, about 10.4% w/w,about 10.5% w/w, about 10.6% w/w, about 10.7% w/w, about 10.8% w/w,about 10.9% w/w, about 11.0% w/w, about 11.1% w/w, about 11.2% w/w,about 11.3% w/w, about 11.4% w/w, about 11.5% w/w, about 11.6% w/w,about 11.7% w/w, about 11.8% w/w, about 11.9% w/w, about 12.0% w/w,about 12.1% w/w, about 12.2% w/w, about 12.3% w/w, about 12.4% w/w, orabout 12.5% w/w of the total solids used to prepare the oral liquidcomposition.

In some embodiments of the oral liquid composition, the paraben is orincludes methylparaben, ethylparaben, propylparaben, or butylparaben. Incertain embodiments, the paraben is present in an amount sufficient toprovide a stable oral liquid composition, for example, providinganti-microbial activity that prevents growth and/or spread of bacteriaand molds. In various embodiments, the paraben is present in aconcentration of from about 1 mg/mL to about 3 mg/mL of the oral liquidcomposition, or in any concentration or within any concentration rangesubsumed therein. In certain embodiments, the paraben is present in aconcentration of from about 0.5 mg/mL to about 4 mg/mL, 0.6 mg/mL toabout 3.9 mg/mL, 0.7 mg/mL to about 3.8 mg/mL, 0.8 mg/mL to about 3.7mg/mL, about 0.9 mg/mL to about 3.6, about 1.1 mg/mL to about 2.9 mg/mL,about 1.2 mg/mL to about 2.8 mg/mL, about 1.3 mg/mL to about 2.7 mg/mL,about 1.4 mg/mL to about 2.6 mg/mL, or about 1.5 mg/mL to about 2.5mg/mL of the oral liquid composition.

In some embodiments of the oral liquid composition, the paraben is orincludes methylparaben. In certain embodiments, methylparaben is presentin a concentration of from about 1.8 mg/mL to about 2.2 mg/mL of theoral liquid composition, or in any concentration or within anyconcentration range subsumed therein. In certain embodiments, themethylparaben is present in a concentration of from about 1.1 mg/mL toabout 2.9 mg/mL, about 1.2 mg/mL to about 2.8 mg/mL, about 1.3 mg/mL toabout 2.7 mg/mL, about 1.4 mg/mL to about 2.6 mg/mL, about 1.5 mg/mL toabout 2.5 mg/mL, about 1.7 mg/mL to about 2.3 mg/mL, or about 1.9 mg/mLto about 2.1 mg/mL of the oral liquid composition. In variousembodiments, methylparaben is present in a concentration of about 1.8mg/mL, about 1.9 mg/mL, about 2.0 mg/mL, about 2.1 mg/mL, or about 2.2mg/mL of the oral liquid composition.

In some embodiments, the paraben is present in a concentration of fromabout 5% w/w to about 15% w/w of the total solids used to prepare theoral liquid composition, or in any concentration or within anyconcentration range subsumed therein. In certain embodiments, theparaben is present in a concentration of from about 9% w/w to about 13%w/w of the total solids used to prepare the oral liquid composition. Incertain embodiments, the paraben is present in a concentration of fromabout 4% w/w to about 16% w/w, about 4.5% w/w to about 15.5% w/w, about6% w/w to about 14% w/w, about 7% w/w to about 13% w/w, about 8% w/w toabout 15% w/w, about 9% w/w to about 14% w/w, about 10% w/w to about 13%w/w, about 10.5% w/w to about 11.5% w/w, or about 11% w/w to about 13%w/w of the total solids used to prepare the oral liquid composition. Inyet other embodiments, the paraben is present in a concentration of fromabout 10% w/w to about 12% w/w of the total solids used to prepare theoral liquid composition.

In other embodiments, methylparaben is present in a concentration offrom about 9.5% w/w to about 12.5% w/w of the total solids used toprepare the oral liquid composition, or in any concentration or in anyconcentration range subsumed therein. In certain embodiments,methylparaben is present in a concentration of from about 9.0% w/w toabout 13% w/w, about 9.1% w/w to about 12.9% w/w, about 9.2% w/w toabout 12.8% w/w, about 9.3% w/w to about 12.7% w/w, about 9.4% w/w toabout 12.6% w/w, about 9.6% w/w to about 12.5% w/w, or about 9.7% w/w toabout 12.4% w/w, about 9.8% w/w to about 12.4% w/w, about 9.9% w/w toabout 12.3% w/w, or about 10% w/w to about 13% w/w of the total solidsused to prepare the oral liquid composition. In some embodiments,methylparaben is present in a concentration of about 9.5% w/w, about9.6% w/w, about 9.7% w/w, about 9.8% w/w, about 9.9% w/w, about 10.0%w/w, about 10.1% w/w, about 10.2% w/w, about 10.3% w/w, about 10.4% w/w,about 10.5% w/w, about 10.6% w/w, about 10.7% w/w, about 10.8% w/w,about 10.9% w/w, about 11.0% w/w, about 11.1% w/w, about 11.2% w/w,about 11.3% w/w, about 11.4% w/w, about 11.5% w/w, about 11.6% w/w,about 11.7% w/w, about 11.8% w/w, about 11.9% w/w, about 12.0% w/w,about 12.1% w/w, about 12.2% w/w, about 12.3% w/w, about 12.4% w/w, orabout 12.5% w/w of the total solids used to prepare the oral liquidcomposition.

In some embodiments of the oral liquid composition, the mole ratio ofcitrate salt to valsartan is from about 3:1 to about 4:1. In certainembodiments, the mole ratio of citrate salt to valsartan is about 3:1,about 3.1:1, about 3.2:1, about 3.3:1, about 3.4:1 about 3.5:1, about3.6:1, about 3.7:1, about 3.8:1, about 3.9:1, or about 4:1. In variousembodiments, the mole ratio of citrate salt to valsartan is about 3.7:1.

In some embodiments of the oral liquid composition, the mole ratio ofsorbate salt to valsartan is from about 1:1 to about 2:1. In certainembodiments, the mole ratio of sorbate salt to valsartan is about 1:1,about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about1.6:1, about 1.7:1, about 1.8:1, about 1.9:1, about 2:1, about 2.1:1,about 2:1.1, or about 2.1:1.1. In various embodiments, the mole ratio ofsorbate salt to valsartan is about 1.5:1.

In some embodiments of the oral liquid composition, the mole ratio ofparaben to valsartan is from about 1:1 to about 2:1. In certainembodiments, the mole ratio of paraben to valsartan is about 1:1, about1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1,about 1.7:1, about 1.8:1, about 1.9:1, about 2:1, about 2.1:1, about2:1.1, or about 2.1:1.1. In various embodiments, the mole ratio ofparaben to valsartan is about 1.4:1.

In some embodiments of the oral liquid composition, the mole ratio ofcitrate salt to sorbate salt is from about 2:1 to about 3:1. In certainembodiments, the mole ratio of citrate salt to sorbate salt is about2:1, about 2.1:1, about 2.2:1, about 2.3:1, about 2.4:1, about 2.5:1,about 2.6:1, about 2.7:1, about 2.8:1, about 2.9:1, about 2.9:1.1, about3:1, about 3:1.1, about 3.1:1, or about 3.1:1.1. In various embodiments,the mole ratio of citrate salt to sorbate salt is about 2.6:1.

In some embodiments of the oral liquid composition, the mole ratio ofcitrate salt to paraben is from about 2:1 to about 3:1. In certainembodiments, the mole ratio of citrate salt to paraben is about 2:1,about 2.1:1, about 2.2:1, about 2.3:1, about 2.4:1, about 2.5:1, about2.6:1, about 2.7:1, about 2.8:1, about 2.9:1, about 2.9:1.1, about 3:1,about 3:1.1, about 3.1:1, or about 3.1:1.1. In various embodiments, themole ratio of citrate salt to paraben is about 2.6:1.

In some embodiments of the oral liquid composition, the mole ratio ofsorbate salt to paraben is from about 0.5:1 to about 1.5:1. In certainembodiments, the mole ratio of sorbate salt to paraben is from about0.6:1, about 0.7:1, about 0.8:1, about 1.1:1, about 1.2:1, about 1.3:1,1.4:1, about 1.6:1, about 1.7:1, about 1.8:1, about 1.9:1, or about 2:1.In various embodiments, the mole ratio of sorbate salt to paraben isabout 1:1.

In some embodiments, the oral liquid composition can comprise one ormore additional excipients, including but not limited to, sweeteners,flavoring agents, stabilizers, coloring agents, thickeners and the like.Additional excipients can be selected based on function andcompatibility with the oral liquid composition disclosed herein and maybe found, for example, in Remington: The Science and Practice ofPharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995);Hoover, John E., Remington's Pharmaceutical Sciences, (Easton, Pa.: MackPublishing Company, 1975); Liberman, H. A. and Lachman, L., Eds.,Pharmaceutical Dosage Forms (New York, N.Y.: Marcel Decker, 1980); andPharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed.(Lippincott Williams & Wilkins, 1999), Kibbe, Arthur H., “Handbook ofPharmaceutical Excipients” (3rd ed.) (2000) all of which are hereinincorporated by reference in their entirety.

One or more sweeteners or sweetening agents can be used in the liquidcomposition and can include any compounds that provide a sweet taste,including, for example, natural and synthetic sugars, natural andartificial sweeteners, natural extracts and any material that initiatesa sweet sensation in a subject. In some embodiments, the oral liquidcomposition disclosed herein comprises one or more sweeteners. In someembodiments, solid, powder sweeteners are used in the liquid compositiondisclosed herein. In other embodiments, sweeteners in liquid form, alsoreferred to as syrups, are used in the oral liquid composition disclosedherein.

Suitable sweeteners for inclusion in the oral liquid compositioninclude, but are not limited to, glucose, fructose, sucrose, xylitol,tagatose, sucralose, maltitol, isomaltulose, ISOMALT™ (hydrogenatedisomaltulose), lactitol, sorbitol, mannitol, erythritol, trehalose,maltodextrin, polydextrose, and the like. Other sweeteners that may beincluded in the compositions herein include, for example, glycerin,inulin, erythritol, maltol, acesulfame and salts thereof (e.g.,acesulfame potassium), alitame, aspartame, neotame, sodium cyclamate,saccharin and salts thereof (e.g., saccharin sodium or saccharincalcium), neohesperidin dihydrochalcone, stevioside, thaumatin, and thelike. Sweeteners can be used in the form of crude or refined products,such as, for example, hydrogenated starch hydrolysates, maltitol syrup,high fructose corn syrup, etc., and as branded products, e.g., SWEET AM™liquid (Product Code 918.003-propylene glycol, ethyl alcohol, andproprietary artificial flavor combination, Flavors of North America),SWEET AM™ powder (Product Code 918.005—maltodextrin, sorbitol, andfructose combination and Product Code 918.010—water, propylene glycol,sorbitol, fructose, and proprietary natural and artificial flavorcombination, Flavors of North America), PROSWEET™ (1-10% proprietaryplant/vegetable extract and 90-99% dextrose combination, Virginia Dare),MALTISWEET™ (maltitol solution, Ingredion) and SORBO™ (sorbitol andsorbitol/xylitol solution, SPI Polyols), INVERTOSE™ (high fructose cornsyrup, Ingredion), and ORA-SWEET™ sugar-free flavored syrup (PaddockLaboratories, Inc.), Sweeteners can be used singly or in combinations oftwo or more. In some embodiments, the sweetener is sucralose. Suitableconcentrations of different sweeteners can be selected based onpublished information, manufacturers' data sheets, and/or by routinetesting.

In some embodiments of the oral liquid composition, the sweetener ispresent in an amount equivalent to about 0.01% w/w to about 5% w/w ofthe total solids used to prepare the liquid composition, or in anyconcentration or within any concentration range subsumed therein. Incertain embodiments, the sweetener is present in an amount equivalent toabout 0.5% w/w to about 2.5% w/w of the total solids used to prepare theliquid composition. In certain embodiments, the sweetener is present ina concentration of from about 0.2% w/w to about 4.5% w/w, about 0.3% w/wto about 4% w/w, about 0.4% w/w to about 3.5% w/w, about 0.5% w/w toabout 3% w/w, or about 0.6% w/w to about 2.6% w/w. In variousembodiments, the sweetener is present in a concentration of from about1% w/w to about 2% w/w of the total solids used to prepare the liquidcomposition.

In some embodiments of the oral liquid composition, the sweetener is orincludes sucralose. In certain embodiments, sucralose is present in theoral liquid composition in a concentration of from about 0.1 mg/mL toabout 0.3 mg/mL, or in any concentration or within any concentrationrange subsumed therein. In various embodiments, sucralose is present inthe oral liquid composition in a concentration of a range of from about0.05 mg/mL to about 0.5 mg/mL, about 0.07 mg/mL to about 0.45 mg/mL,about 0.09 mg/mL to about 0.4 mg/mL, about 0.14 mg/mL, to about 0.35mg/mL, about 0.16 mg/mL, to about 0.3 mg/mL, about 0.17 mg/mL to about0.27 mg/mL, or about 0.13 mg/mL to about 0.20 mg/mL. In certainembodiments, sucralose is present in a concentration of from about 0.15mg/mL to about 0.25 mg/mL. In various embodiments, sucralose is presentin a concentration of about 0.15 mg/mL, about 0.16 mg/mL, about 0.17mg/mL, about 0.18 mg/mL, about 0.19 mg/mL, about 0.20 mg/mL, about 0.21mg/mL, about 0.22 mg/mL, about 0.23 mg/mL, about 0.24 mg/mL, or about0.25 mg/mL.

In some embodiments of the oral liquid composition, sucralose is presentin a concentration of from about 0.5% w/w to about 2% w/w of the totalsolids used to prepare the oral liquid composition, or in anyconcentration or within any concentration range subsumed therein. Incertain embodiments, sucralose is present in a concentration of fromabout 0.9% w/w to about 1.3% w/w of the total solids used to prepare theoral liquid composition. In various embodiments, the oral liquidcomposition includes sucralose in a concentration range, by weight, offrom about 0.3% w/w to about 3% w/w, about 0.4% w/w to about 2.7% w/w,about 0.4% w/w to about 2.5% w/w, about 0.6% w/w to about 2% w/w, about0.7% w/w to about 1.8% w/w, about 0.8% w/w to about 1.5% w/w, or about1% w/w to about 2.1% w/w of the total solids used to prepare the oralliquid composition. In various embodiments, sucralose is present in aconcentration of about 0.9% w/w, about 1.0% w/w, about 1.1% w/w, about1.2% w/w, or about 1.3% w/w of the total solids used to prepare the oralliquid composition.

One or more flavoring agents can be used to enhance the taste or aromaof the oral liquid composition. Suitable natural or synthetic flavoringagents can be selected from standard reference books, for exampleFenaroli's Handbook of Flavor Ingredients, 3rd edition (1995).Non-limiting examples of suitable natural flavors for inclusion in theoral liquid composition, some of which can readily be simulated withsynthetic agents or combinations thereof, include almond, anise, apple,apricot, bergamot, blackberry, blackcurrant, blueberry, cacao, caramel,cherry, cinnamon, clove, coffee, coriander, cranberry, cumin, dill,eucalyptus, fennel, fig, ginger, grape, grapefruit, guava, hop, lemon,licorice, lime, malt, mandarin, molasses, nutmeg, orange, peach, pear,peppermint, pineapple, raspberry, rose, spearmint, strawberry,tangerine, tea, tutti-frutti, vanilla, wintergreen, and the like. Incertain embodiments, flavoring agents include cherry, grape, andbubblegum. In some embodiments, the liquid composition comprises a grapeflavoring agent.

In some embodiments, the flavoring agent is present in a concentrationof from about 1 mg/mL to about 5 mg/mL of the oral liquid composition,or in any concentration or within any concentration range subsumedtherein. In certain embodiments, the flavoring agent is present in theoral liquid composition in a concentration ranging from about 1.4 mg/mLto about 3 mg/mL, about 2 mg/mL to about 4 mg/mL, about 2.2 mg/mL toabout 3.7 mg/mL, or about 2.8 mg/mL to about 3.7 mg/mL. In variousembodiments, the flavoring agent is present in the oral liquidcomposition in a concentration ranging from about 2.5 mg/mL to about 3.5mg/mL

Coloring agents can be included in the composition herein foridentification and/or aesthetic purposes. Suitable coloring agentsinclude, but are not limited to, FD&C Red No. 3, FD&C Red No. 20, FD&CRed No. 40, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&COrange No. 5, caramel, ferric oxide, or mixtures thereof.

The oral liquid compositions disclosed herein may be prepared in theforms of, for example and without limitation, aqueous solutions,nonaqueous solutions, juices, elixirs, and the like. Despite valsartanhaving low solubility, the oral liquid compositions herein surprisinglyare solutions rather than suspensions, wherein no active ingredient ispresent as particulate matter or in a solid form in the compositions.Fully solubilizing the active ingredients, such as valsartan, in theoral liquid compositions herein provides advantages over their partiallysolubilized counterparts (e.g., suspensions, slurries etc.). Suchadvantages include, for example, higher drug absorption and drugpermeability, lending to improved bioavailability. However, lowsolubility active ingredients, such as valsartan, typically posesignificant challenges to formulating liquid compositions in which theactive ingredient is completely soluble and remains completely solubleuntil administration. The oral liquid compositions disclosed hereinovercome those challenges.

Suitable liquid vehicles for use in the oral liquid compositions hereinare selected based on imparting desired qualities, including forexample, clarity, nontoxicity, acceptable viscosity, compatibility withexcipients, chemical inertness, palatability, acceptable odor and color,and economy. Exemplary liquid vehicles include, for example, water,ethyl alcohol, glycerin, propylene glycol, syrup (sugar or othersweetener based substance, e.g., ORA-SWEET™ SF sugar-free flavoredsyrup), juices (apple, grape, orange, cranberry, cherry, tomato and thelike), other beverages (tea, coffee, soft drinks, milk and the like),oils (olive, soybean, corn, mineral, castor and the like), andcombinations or mixtures thereof. Certain liquid vehicles, e.g., one ormore oils and water, can be combined to form emulsions for inclusion inthe oral liquid composition. In some embodiments, water is used as avehicle in the oral liquid composition. In certain embodiments, a syrupis used as a vehicle in the oral liquid composition. In variousembodiments, a juice is used as a vehicle in the oral liquidcomposition.

In some embodiments, the oral liquid composition disclosed herein ishomogenous. As used herein, a “homogenous liquid” refers to a liquidthat is uniform in appearance, identity, consistency and drugconcentration per volume. Non-homogenous liquids include such liquidsthat have varied coloring, and/or viscosity, as well as non-uniform drugconcentration in each unit volume. Homogeneity in liquids is assessed byqualitative identification or appearance tests and/or quantitative HighPerformance Liquid Chromatography (HPLC) testing or the like. Exemplaryqualitative testing includes visual inspection of the resultant liquidfor air bubbles and/or undissolved solids which may cause variabledosing. Analytical HPLC testing can also determine drug concentrationuniformity by examining aliquots of certain volume sections (e.g., 5 or10 mL from the top, middle and bottom of a 150 mL bottle). The mixingmethods and excipients disclosed herein are selected to impart ahomogenous quality to the oral liquid composition.

Mixing methods encompass any type of mixing resulting in a homogenousoral liquid composition. Mixing can include one or more of stirring,shaking, swirling, agitating, or inverting. In some embodiments,individual components of the oral liquid composition are addedsequentially, concurrently, or in any combination thereof to a liquidvehicle. In some embodiments, individual components are addedsequentially, one at a time. In certain embodiments, the sequentialaddition of individual components includes mixing for a certain timeinterval after each or some of the sequential additions. In variousembodiments, all individual components are added at the same time to aliquid vehicle and then mixed for a certain time interval.

In various embodiments disclosed herein, mixing occurs for certain timeintervals, such as, for example, about 10 seconds, about 20 seconds,about 30 seconds, about 40 seconds, about 50 seconds, about 60 seconds,about 90 seconds, about 2 minutes, about 2.5 minutes, about 3 minutes,about 3.5 minutes, about 4 minutes, about 4.5 minutes, about 5 minutes,about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes orabout 10 minutes or more. In certain embodiments, mixing occurs in timeinterval ranges, for example, from about 10 seconds to about 60 seconds,about 30 seconds to about 60 seconds, about 1 minute to about 10minutes, about 3 minutes to about 7 minutes, or about 5 minutes to about10 minutes. In embodiments where there are two or more mixing steps, thetime intervals for each mixing can be the same or different. In someembodiments, the resulting oral liquid composition is allowed to standfor a set amount of time, for example, about 5 minutes, about 10minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50minutes, about 60 minutes, about 90 minutes, about 120 minutes, or moreto allow any resulting air bubbles arising from mixing to dissipate.

The oral liquid compositions herein are stable under various storageconditions, including refrigerated and ambient conditions. As usedherein. the term “stable” refers to the oral liquid compositionretaining at least about 90% of the initial valsartan amount, retainingat least about 95% of the initial valsartan amount, or retaining atleast about 98% of the initial valsartan amount at the end of a givenstorage period under specified storage conditions. The term “stable” canalso refer to an oral liquid composition including about 1% w/w or lesstotal impurities or related substances, about 0.5% w/w or less totalimpurities or related substances, or about 0.4% w/w or less totalimpurities or related substances at the end of a given storage periodunder specified storage conditions. The term “stable” can also refer toan oral liquid composition having about 0.5% w/w or less individualimpurities or related substances, or 0.2% w/w or less individualimpurities or related substances at the end of a given storage periodunder specified storage conditions. The term “stable” can also refer toan oral liquid composition having less than about 10² total aerobicmicrobial count at the end of a given storage period under specifiedstorage conditions. The term “stable” can also refer to an oral liquidcomposition having less than 10¹ total combined yeast and mold count atthe end of a given storage period under specified storage conditions.The term “stable” can also refer to the absence or non-detection ofEscherichia coli and/or Burkholderia cepacia within the oral liquidcomposition following a given storage period under specified storageconditions.

In some embodiments, the oral liquid composition herein is stable underrefrigerated (5° C.±3° C.) and ambient conditions (25° C.±2° C. and40%±5% RH) for at least 12 weeks, at least 16 weeks, at least 20 weeks,at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36weeks, at least 48 weeks, at least 52 weeks, at least 60 weeks, at least72 weeks, at least 84 weeks, at least 96 weeks, at least 104 weeks, atleast 108 weeks, or at least 120 weeks. In certain embodiments, the oralliquid composition herein is stable under refrigerated (5° C.±3° C.) andambient conditions (25° C.±2° C. and 40%±5% RH) for up to 12 weeks, upto 16 weeks, up to 20 weeks, up to 24 weeks, up to 28 weeks, up to 32weeks, up to 36 weeks, up to 48 weeks, up to 52 weeks, up to 60 weeks,up to 72 weeks, up to 84 weeks, up to 96 weeks, up to 104 weeks, up to108 weeks or up to 120 weeks. Ambient conditions, also referred to ascontrolled room temperature (CRT) conditions, include temperature and/orrelative humidity that are at ambient levels (e.g., 25° C.±2° C. and40%±5% RH). In some instances, ambient conditions are at about 20° C.,about 21° C., about 22° C., about 23° C., about 24° C., about 25° C.,about 26° C., about 27° C., about 28° C., about 29° C., or about 30° C.In certain embodiments, ambient conditions include a range oftemperatures, all at 40%±5% relative humidity, for example, from about23° C. to about 27° C., about 22° C. to about 28° C., or about 24° C. toabout 26° C. In certain embodiments, ambient conditions include a rangeof relative humidities, all at 25° C.±2° C., for example, from about 37%to about 42%, about 34% to about 47%, or about 36% to about 46% relativehumidity. In other instances, an ambient condition is about 45% RH,about 50% RH, about 55% RH, about 60% RH, or about 65% RH. Refrigeratedconditions include temperatures and/or relative humidity in typicalrefrigeration units (e.g., 5±3° C.). In certain embodiments,refrigerated conditions include a range of temperatures, for example,from about 1° C. to about 10° C., about 2° C. to about 9° C., about 3°C. to about 8° C., or about 1° C. to about 8° C. In some instances,refrigerated conditions are at about 2° C., about 3° C., about 4° C.,about 5° C., about 6° C., about 7° C., or about 8° C.

In further embodiments, the stable oral liquid composition disclosedherein, stored under ambient or refrigerated conditions for a specifiedstorage period, provides similar, consistent, or equivalentpharmacokinetic parameters as an oral liquid composition that isformulated immediately prior to administration to a subject (i.e.,freshly made). In other words, the oral liquid composition disclosedherein exhibits high stability after a specified storage period toprovide similar, consistent, or equivalent pharmacokinetic parameters asa freshly made oral liquid composition. For example, a 104-week stableoral liquid composition, stored under controlled room temperatureconditions, provides pharmacokinetic parameters similar, consistent, orequivalent to an oral liquid composition made five minutes prior toadministration. Pharmacokinetic parameters for valsartan includeC_(max), T_(max), AUC_(last), AUC_(inf), T_(1/2), and C_(last).

In some instances, administration of an oral liquid composition hereinprovides one or more pharmacokinetic parameters within 80% to 125%, 80%to 120%, 85% to 125%, 90% to 110% of the same parameter(s) obtained fromadministration of a freshly made liquid composition after the oralliquid composition herein has been stored at ambient conditions of 25°C.±2° C. and 40%±5% relative humidity for up to 12 weeks, up to 16weeks, up to 20 weeks, up to 24 weeks, up to 28 week, up to 32 weeks, upto 36 weeks, up to 48 weeks, up to 52 weeks, up to 60 weeks, up to 72weeks, up to 84 weeks, up to 96 weeks, up to 104 weeks, up to 108 weeksor at least 120 weeks, after preparation.

Methods of Treatment:

In another aspect, methods of treatment comprising administering an oralliquid composition disclosed herein to a subject in need thereof areprovided are. In some embodiments, an oral liquid composition herein canbe used to treat hypertension in a subject. Hypertension, as usedherein, includes both primary (essential) hypertension or secondaryhypertension. Hypertension can be classified in cases when bloodpressure values are greater than or equal to 140/90 (systolic/diastolic)mm Hg in an adult subject. In other embodiments, the oral liquidcomposition disclosed herein treats primary (essential) hypertension ina subject. In yet other embodiments, the oral liquid composition hereintreats secondary hypertension in a subject. In certain embodiments, thesubject is a pediatric subject. Pediatric hypertension can be classifiedin cases where the child's blood pressure is greater than the 95thpercentile for the patient's age, sex and height. In some embodiments,the subject is a geriatric subject. Hypertension in geriatric patientsis defined similarly to that in adult patients, i.e., blood pressurevalues greater than or equal to 140/90 (systolic/diastolic) mm Hg.

In some embodiments, the oral liquid compositions herein can be used totreat heart failure. In certain embodiments, the oral liquidcompositions herein can be used to reduce cardiovascular mortality inclinically stable patients with left ventricular failure or leftventricular dysfunction following myocardial infarction.

Dosing:

In one aspect, the oral liquid compositions herein are used for thetreatment of diseases and conditions disclosed herein. In addition, amethod for treating any of the diseases or conditions disclosed hereinfor a subject in need of such treatment involves administration oftherapeutically effective amounts of the oral liquid compositions hereinto the subject.

Dosages of the oral liquid compositions disclosed herein can bedetermined by any suitable method. Maximum tolerated dose (MTD) andmaximum response dose (MRD) for valsartan can be determined viaestablished animal and human experimental protocols. For example,toxicity and therapeutic efficacy of valsartan can be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, including, but not limited to, determination of the LD₅₀ (thedose lethal to 50% of the population) and the ED₅₀ (the dosetherapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is known as the therapeuticindex, and it can be expressed as a ratio between LD₅₀ and ED₅₀.Valsartan dosages exhibiting high therapeutic indices are desirable. Thedata obtained from cell culture assays and animal studies can be used informulating a range of dosage for use in humans. The dosage of suchcompounds lies preferably within a range of circulating concentrationsthat include the ED₅₀ with minimal toxicity. The dosage may vary withinthis range depending upon the dosage form employed and the route ofadministration utilized. Additional relative dosages, represented as apercent of maximal response or of maximum tolerated dose, are readilyobtained via these protocols.

In some embodiments, the dose of valsartan for treating adulthypertension in the oral liquid composition is about 80 mg or about 160mg once daily. In certain embodiments, valsartan can be administeredover a dose range of 80 mg to 320 mg daily, administered once a day fortreating adult hypertension. In various embodiments, valsartan in theoral liquid composition can be administered over a dose range from about70 mg to about 170 mg, about 75 mg to about 165 mg, about 85 mg to about155 mg, about 90 mg to about 150 mg, about 95 mg to about 140 mg, about70 mg to about 330 mg, about 90 mg to about 300 mg, about 100 mg toabout 280 mg, about 120 mg to about 250 mg, about 70 mg to about 325 mg,or about 85 mg to about 310 mg daily, administered once a day fortreating adult hypertension.

In some embodiments, the dose of valsartan for treating pediatrichypertension in the oral liquid composition is about 1.3 mg/kg oncedaily, up to about 40 mg total. In other embodiments, valsartan in theoral liquid composition can be administered over a dose range of about1.3 to about 2.7 mg/kg once daily, up to about 40 mg to about 160 mgtotal for treating pediatric hypertension. In certain embodiments,valsartan in the oral liquid composition can be administered over a doserange of about 1.1 to about 2.8 mg/kg, about 1.5 mg/kg to about 2.5mg/kg or about 1.7 to about 2.2 mg/kg once daily. In certain embodimentsvalsartan can be administered over a range of about 30 mg to about 170mg, about 50 mg to about 150 mg, 70 mg to about 130 mg, 80 mg to about120 mg, 90 mg to about 110 mg, or 45 mg to about 155 mg total daily, fortreating pediatric hypertension.

In other embodiments, the dose of valsartan in the oral liquidcomposition for treating heart failure is about 40 mg twice daily. Inyet other embodiments, valsartan in the oral liquid composition can beadministered over a dose range of about 40 mg to about 160 mg twicedaily for treating heart failure. In certain embodiments, valsartan canbe administered over a dose range of about 30 mg to about 170 mg, about50 mg to about 150 mg, 70 mg to about 130 mg, 80 mg to about 120 mg, 90mg to about 110 mg, or 45 mg to about 155 mg twice daily for treatingheart failure.

In other embodiments, the dose of valsartan in the oral liquidcomposition for reducing cardiovascular mortality in clinically stablepatients with left ventricular failure or left ventricular dysfunctionfollowing myocardial infarction is about 20 mg twice daily. In otherembodiments, valsartan in the oral liquid composition can beadministered over a dose range of about 20 mg to about 160 mg twicedaily for reducing cardiovascular mortality in clinically stablepatients with left ventricular failure or left ventricular dysfunctionfollowing myocardial infarction. In certain embodiments, valsartan inthe oral liquid composition can be administered over a dose range ofabout 10 mg to about 170 mg, about 35 mg to about 140 mg, about 50 mg toabout 130 mg, about 60 mg to about 110 mg, about 70 mg to about 100 mg,about 25 mg to about 155 mg, or about 30 mg to about 145 mg, twice dailyfor reducing cardiovascular mortality in clinically stable patients withleft ventricular failure or left ventricular dysfunction followingmyocardial infarction.

In some embodiments, the oral liquid composition is provided foradministration to a human subject at a maximum tolerated dose (MTD) ofvalsartan. In certain embodiments, the amount of valsartan in the oralliquid composition administered to a human subject is from about 10% toabout 90% of the MTD, from about 25% to about 75% of the MTD, or about50% of the MTD. In certain embodiments, the amount of the oral liquidcomposition administered to a human subject ranges from about 20% toabout 80% of the MTD, about 30% to about 70% of the MTD, about 40% toabout 60% of the MTD, or about 20% to about 60% of the MTD. In certainother embodiments, the amount of the oral liquid compositionadministered is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%,45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or higher,or any range derivable therein, of the MTD for valsartan.

In some embodiments, the oral liquid composition is provided in a dosagethat is similar, comparable, or equivalent to a dosage of a knownvalsartan tablet formulation. In other embodiments, the oral liquidcomposition is provided in a dosage that provides similar, comparable,or equivalent pharmacokinetic parameters (e.g., AUC, C_(max), T_(max),C_(min), T_(1/2)) as a dosage of a commercially available valsartantablet formulation. Similar, comparable, or equivalent pharmacokineticparameters, in some instances, refer to within 80% to 125%, 80% to 120%,85% to 125%, 90% to 110%, or increments therein, of the given values. Itshould be recognized that the ranges can, but need not be, symmetrical,e.g., 85% to 105%.

The term “AUC” as used herein refers to the integral of theconcentration-time curve. The terms “AUC_(last)” and “AUC_(0→t)” as usedherein refer to the area under a plasma concentration versus time curvefrom time 0 to the time of the last measured concentration of drugwithin the plasma. The terms “AUC_(inf)” and “AUC_(0→∞).” as used hereinrefer to the area under a plasma concentration versus time curve fromtime 0 to infinity.

Certain non-limiting embodiments of the oral liquid composition of thepresent disclosure include administration of an oral liquid compositionincluding 80 mL of valsartan (4 mg/mL, a total of 320 mg valsartan)wherein the composition results in a valsartan AUC_(last) ranging fromabout 33,878 ng*h/mL to about 70,475 ng*h/mL. More generally, certainnon-limiting embodiments of administration of 80 mL of the oral liquidcomposition including 4 mg/mL valsartan (total of 320 mg valsartan)result in a valsartan AUC_(last) ranging from about 25,000 ng*h/mL toabout 78,000 ng*h/mL, or has any AUC_(last) value or falls within anyAUC_(last) range subsumed therein, such as, for example, about 26,000ng*h/mL to about 77,000 ng*h/mL, about 27,000 ng*h/mL to about 76,000ng*h/mL, about 28,000 ng*h/mL to about 75,000 ng*h/mL, about 29,000ng*h/mL to about 74,000 ng*h/mL, about 30,000 ng*h/mL to about 73,000ng*h/mL, about 31,500 ng*h/mL to about 72,500 ng*h/mL, about 32,000ng*h/mL to about 72,000 ng*h/mL, about 32,500 ng*h/mL to about 71,500ng*h/mL, about 33,000 ng*h/mL to about 71,000 ng*h/mL, about 33,500ng*h/mL to about 70,500 ng*h/mL, about 34,000 ng*h/mL to about 70,000ng*h/mL, about 34,500 ng*h/mL to about 69,500 ng*h/mL, about 35,000ng*h/mL to about 69,000 ng*h/mL, about 37,500 ng*h/mL to about 68,000ng*h/mL, or about 38,000 ng*h/mL to about 67,000 ng*h/mL.

Certain non-limiting embodiments of the oral liquid composition of thepresent disclosure include administration of an oral liquid compositionincluding 80 mL of valsartan (4 mg/mL, a total of 320 mg valsartan)wherein the composition results in a valsartan AUC_(inf) ranging fromabout 35,162 ng*h/mL to about 72,130 ng*h/mL. More generally, certainnon-limiting embodiments of administration of 80 mL of the oral liquidcomposition including 4 mg/mL valsartan (total of 320 mg valsartan)result in a valsartan AUC_(inf) ranging from about 30,000 ng*h/mL toabout 78,000 ng*h/mL, or has any AUC_(inf) value or falls within anyAUC_(inf) range subsumed therein, such as, for example, about 32,500ng*h/mL to about 77,000 ng*h/mL, about 33,000 ng*h/mL to about 76,000ng*h/mL, about 33,500 ng*h/mL to about 75,500 ng*h/mL, about 34,000ng*h/mL to about 75,000 ng*h/mL, about 34,500 ng*h/mL to about 77,000ng*h/mL, about 34,750 ng*h/mL to about 76,000 ng*h/mL, about 35,000ng*h/mL to about 75,000 ng*h/mL, about 36,000 ng*h/mL to about 74,000ng*h/mL, about 37,000 ng*h/mL to about 73,000 ng*h/mL, about 38,000ng*h/mL to about 72,000 ng*h/mL, about 39,000 ng*h/mL to about 71,000ng*h/mL, about 40,000 ng*h/mL to about 70,000 ng*h/mL, about 45,000ng*h/mL to about 76,000 ng*h/mL, about 50,000 ng*h/mL to about 76,500ng*h/mL, about 55,000 ng*h/mL to about 77,000 ng*h/mL, about 60,000ng*h/mL to about 76,000 ng*h/mL, or about 65,000 ng*h/mL to about 76,500ng*h/mL.

The pharmacokinetic parameter C_(max) refers to the maximum (i.e., peak)serum concentration of a specific compound in the body of a subjectafter a pharmaceutical composition or compound has been administrated tothe subject. The term “C_(last)” as used herein refers to the lastobserved quantifiable concentration of a specific compound in the bodyof a subject after a pharmaceutical composition or compound has beenadministrated to the subject.

One non-limiting embodiment herein is directed to administration of anoral liquid composition including 80 mL of valsartan (4 mg/mL, a totalof 320 mg valsartan) wherein the composition results in a valsartanC_(max) ranging from about 8,281 ng/mL to 14,714 ng/mL in the subjectfollowing administration of the oral liquid composition. In certainnon-limiting embodiments, the valsartan C_(max) achieved following oraladministration of the oral liquid composition to a subject is within therange of from about 7,500 ng/mL to about 16,000 ng/mL, or has anyC_(max) value or falls within any C_(max) range subsumed therein, suchas, for example, from about 7,700 ng/mL to about 17,000 ng/mL, about7,800 ng/mL to about 16,500 ng/mL, about 7,850 ng/mL to about 16,250ng/mL, about 7,900 ng/mL to about 16,000 ng/mL, about 8,000 ng/mL toabout 15,500 ng/mL, about 8,100 ng/mL to about 15,000 ng/mL, about 8,150ng/mL to about 14,900 ng/mL, about 8,200 ng/mL to about 14,800 ng/mL,about 8,250 ng/mL to about 14,750 ng/mL, about 8,300 ng/mL to about14,725 ng/mL, about 8,400 ng/mL to about 14,700 ng/mL, about 8,500 ng/mLto about 14,600 ng/mL, or about 8,900 ng/mL to about 14,500 ng/mL.

The pharmacokinetic parameter T_(max) for a pharmaceutical compositionor compound is the time after administration to a subject at which theC_(max) is observed in the subject. As such, the term “T_(max)” as usedherein refers to the time after administration of a drug when themaximum plasma concentration is reached.

One non-limiting embodiment herein is directed to administration of anoral liquid composition including 80 mL of valsartan (4 mg/mL, a totalof 320 mg valsartan) to a subject, wherein the composition results in avalsartan T_(max) of about 0.66 h to about 2.66 h in the subject. Invarious non-limiting embodiments, following the administration of theoral liquid composition including 80 mL of valsartan (4 mg/mL, a totalof 320 mg valsartan) to a subject, the observed valsartan T_(max) fallswithin the range from about 0.50 h to about 3.3 h, or has any T_(max)value or falls within any T_(max) range subsumed therein, such as, forexample, from about 0.55 h to about 3.2 h, about 0.60 h to about 3.1 h,about 0.65 h to about 3.0 h, about 0.70 h to about 2.9 h, about 0.75 hto about 2.8 h, about 0.80 h to about 2.7 h, about 0.85 h to about 2.6h, about 0.90 h to about 2.5 h, about 1.0 h to about 2.4 h, about 1.1 hto about 2.3 h, about 1.2 h to about 2.2 h, about 1.3 h to about 2.1 h,about 0.50 h to about 2.0 h, about 0.50 h to about 1.0 h, or about 0.4 hto about 2.25 h.

The term “absorptivity factor” as used herein refers to the maximum(i.e., peak) serum concentration of a specific compound in the body of asubject after a pharmaceutical composition or compound has beenadministrated to the subject (C_(max)) divided by the area under thedrug concentration-time curve from time 0 to infinity (AUC_(inf)).

Certain non-limiting embodiments according to the present disclosureinclude administration of an oral liquid composition including 80 mL ofvalsartan (4 mg/mL, a total of 320 mg valsartan) to a subject, whereinthe composition results in an absorptivity factor for valsartan rangingfrom about 0.040 h⁻¹ to about 0.388 h⁻¹ in the subject. In certainnon-limiting embodiments, the absorptivity factor for valsartanresulting following administration of an oral liquid compositionincluding 80 mL of valsartan (4 mg/mL, a total of 320 mg valsartan) to asubject is in a range of from about 0.01 h⁻¹ to 1.0 h⁻¹, or has anyvalue or falls within any range subsumed therein, such as, for example,from about 0.015 h¹ to about 0.90 h⁻¹, from about 0.02 h⁻¹ to about 0.80h⁻¹, from about 0.025 h⁻¹ to about 0.70 h⁻¹, from about 0.03 h⁻¹ toabout 0.60 h⁻¹, from about 0.035 h⁻¹ to about 0.55 h⁻¹, from about 0.04h⁻¹ to about 0.50 h⁻¹, from about 0.045 h⁻¹ to about 0.45 h⁻¹, fromabout 0.05 h⁻¹ to about 0.40 h⁻¹, from about 0.07 h⁻¹ to about 0.35 h⁻¹,from about 0.09 h⁻¹ to about 0.30 h⁻¹, from about 0.1 h⁻¹ to about 0.25h⁻¹, from about 0.20 h⁻¹ to about 0.50 h⁻¹, from about 0.30 h⁻¹ to about0.80 h⁻¹, or from about 0.050 h⁻¹ to about 0.50 h⁻¹.

Administration:

The oral liquid compositions described herein can be administered at adosage disclosed herein or at other appropriate dose levels contemplatedby a medical practitioner. In certain embodiments, the oral liquidcompositions disclosed herein are administered for prophylactic and/ortherapeutic treatments. In certain therapeutic applications, the oralliquid compositions are administered to a patient already suffering froman indication, e.g., hypertension, in a therapeutically effective amountsufficient to cure the disease or at least partially arrest orameliorate the symptoms, e.g., lower blood pressure. Amounts effectivefor this use depend on, for example, the age of the patient, severity ofthe disease, previous therapy, the patient's health status, weight, andresponse to the oral liquid compositions, and are within the judgment ofthe treating physician. Therapeutically effective amounts are optionallydetermined by methods including, but not limited to, a dose escalationclinical trial.

In certain embodiments wherein the patient's condition does not improve,upon the doctor's discretion, the oral liquid composition disclosedherein may be administered chronically, that is, for an extended periodof time, including throughout the duration of the patient's life toameliorate or otherwise control or limit the symptoms of the patient'sdisease. In some embodiments, administration of the oral liquidcomposition continues until complete or partial response of a diseaseoccurs.

In some embodiments, an oral liquid composition herein is administeredto a subject who is in a fasted state. A fasted state refers to thestate of a subject who has gone without food or fasted for a specifiedamount of time. General fasting periods include at least 4 hours, atleast 6 hours, at least 8 hours, at least 10 hours, at least 12 hours,at least 14 hours, and at least 16 hours without food. In certainembodiments, an oral liquid composition herein is administered to asubject who has fasted overnight.

In some embodiments, an oral liquid composition herein is administeredto a subject who is in a fed state. A fed state refers to the state of asubject who has taken food or has had a meal. In certain embodiments, anoral liquid composition is administered to a subject in a fed state 5minutes post-meal, 10 minutes post-meal, 15 minutes post-meal, 20minutes post-meal, 30 minutes post-meal, 40 minutes post-meal, 50minutes post-meal, 1 hour post-meal, 2 hours post-meal, or more. Incertain instances, an oral liquid composition is administered to asubject along with food.

Further Combinations:

In some embodiments, the treatment of certain diseases or conditions(e.g., hypertension, treatment of heart failure and reduction ofcardiovascular mortality in clinically stable patients with leftventricular failure or left ventricular dysfunction following myocardialinfarction) in a subject with the oral liquid compositions disclosedherein encompasses additional therapies and treatment regimens withother active pharmaceutical ingredients. In some embodiments, additionaltherapies and treatment regimens can include sequential or concurrentadministration of a second active ingredient to a subject to treat thesame or different disease or condition being treated with the oralliquid composition. In various embodiments, additional therapies andtreatment regimens include sequential or concurrent administration of asecond active ingredient to a subject to treat adjunct conditionsassociated with the disease or condition or a side effect from the oralliquid composition in the therapy.

Possible additional active ingredients for use in combination with anoral liquid composition as disclosed herein, include, but are notlimited to, diuretics (loop, thiazide, potassium-sparing, and the like),beta blockers (metoprolol, propanolol, pronethalol, and the like), alphablockers (phentolamine, phenoxybenzamine, tamsulosin, prazosin, and thelike), mixed alpha and beta blockers (bucindolol, carvedilol,labetalol), calcium channel blockers (dilitazem, verapamil,dihydropyridines such as nifedipine, amlodipine, etc., and the like),angiotensin II receptor antagonists (saralasin, losartan, eprosartin,irbesartan, and the like), other ACE inhibitors (lisinopril, captopril,quinapril, ramipril, zofenopril, and the like), aldosterone antagonists(eplerenone, spironolactone and the like), vasodilators (hydralazine andthe like), and alpha-2 agonists (clonidine, moxonidine, guanabenz andthe like).

EXAMPLES Example 1. Preparation of Three Oral Liquid CompositionsIncluding Valsartan

Three oral liquid compositions were prepared using the method describedbelow. The following process describes the preparation of compositions#1, #3, and #4, the compositions of which are shown in Table 1 below.

TABLE 1 Compositions of oral liquid compositions #1 #2, and #3, allthree oral liquid compositions including, by weight, 0.4% valsartan (4mg/mL). #1 #3 #4 #1 #3 #4 Ingredient Function % w/v % w/v % w/v mg/mLmg/mL mg/mL Valsartan API 0.4 0.4 0.4 4 4 4 Citric acid, anhydrousBuffer — — — — — — Potassium sorbate Preservative 0.2 0.2 0.1 2 2 1Grape Flavor Flavor 0.3 0.4 0.3 3 4 3 Methylparaben Preservative 0.2 0.20.1 2 2 1 Sodium citrate, dihydrate Buffer 1.2 1.2 1.0 12 12 10Sucralose Sweetener 0.01 0.02 0.02 0.1 0.2 0.2 Poloxamer 188 Solubilizer1.0 1.0 1.0 10 10 10 Propylene Glycol Solubilizer 10.0 10.0 10.0 100 100100 Purified Water Solvent 86.69 86.58 87.08 866.9 865.8 870.8

Unless otherwise noted, all components were added in thequantities/concentrations provided in Table 1 and steps were performedat room temperature. Valsartan was mixed in propylene glycol withstirring until there were no visible valsartan particles in the mixture(“first mixture”). Methylparaben was added to the first mixture andstirred until there were no visible methylparaben particles in thissecond mixture.

In a separate vessel, poloxamer 188 was mixed in water and stirred untilthere were no visible poloxamer 188 particles in this third mixture.Sodium citrate dihydrate was then slowly added to the third mixture andstirred until there were no visible sodium citrate dihydrate particlesin this fourth mixture.

The second mixture (valsartan, propylene glycol and methylparaben) wasslowly added to the fourth mixture (poloxamer 188, water, and sodiumcitrate dihydrate) until the combined mixture was clear.

Potassium sorbate was added to the combined mixture and stirred untilthere were no visible potassium sorbate particles in this fifth mixture.Sucralose was then added to the fifth mixture and stirred until allparticles were dissolved in this final mixture. For preparation ofcomposition #1, water was added quantum satis up to 1000 g to the finalmixture and then flavoring was added to form composition #1. Forcompositions #3 and #4, flavoring was added to the final mixture, andthen water was added quantum satis up to 1000 g to form compositions #3and #4.

Example 2. Preparation of an Oral Liquid Composition Including Valsartan

An oral liquid composition was prepared using the method describedbelow. The following process describes the preparation of composition#2, the composition of which is shown in Table 2 below.

TABLE 2 Oral Liquid Composition #2, including by weight, 0.4% valsartan(4 mg/mL). #2 #2 Ingredient Function % w/v mg/mL Valsartan API 0.4 4Citric acid, anhydrous Buffer 0.2 2 Potassium sorbate Preservative 0.2 2Grape Flavor Flavor 0.3 3 Methylparaben Preservative 0.2 2 Sodiumcitrate, dihydrate Buffer 1.2 12 Sucralose Sweetener 0.03 0.3 Poloxamer188 Solubilizer 1.0 10 Propylene Glycol Solubilizer 10.0 100 PurifiedWater Solvent 86.47 864.7

Unless otherwise noted, all components were added in thequantities/concentrations provided in Table 2 and all steps wereperformed at room temperature. Valsartan was mixed in propylene glycolwith stirring until there were no visible valsartan particles in the(first) mixture. Methylparaben was then added to the first mixture andstirred until there were no visible methylparaben particles in thissecond mixture.

In a separate vessel, poloxamer 188 was mixed in water and stirred untilthere were no visible poloxamer 188 particles in this third mixture.Sodium citrate dihydrate was then slowly added to the third mixture andstirred until there were no visible sodium citrate dihydrate particlesin this fourth mixture. Citric acid anhydrous was then added to thefourth mixture with stirring until there were no visible citric acidanhydrous particles in this fifth mixture.

The second mixture (valsartan, propylene glycol and methylparaben) wasslowly added to the fifth mixture (poloxamer 188, water, sodium citratedihydrate and citric acid anhydrous) with stirring until the combinedmixture was clear.

Potassium sorbate was added to the combined mixture and stirred untilthere were no visible potassium sorbate particles in this sixth mixture.Sucralose was then added to the sixth mixture and stirred until allparticles were dissolved in this final mixture. Flavoring was added tothe final mixture, and then water was added quantum satis up to 1000 gto form composition #2.

Example 3. Preparation of an Oral Liquid Composition Including 0.4%, byWeight, (4 mg/mL) Valsartan

An oral liquid composition including valsartan was prepared using themethod described below. The following process describes the preparationof composition #5, the composition of which is shown in Table 3 below.

TABLE 3 Oral Liquid Composition #5, including by weight, 0.4% valsartan(4 mg/mL). #5 #5 Ingredient Function % w/v mg/mL Valsartan API 0.4 4Citric acid, anhydrous Buffer — — Potassium sorbate Preservative 0.2 2Grape Flavor Flavor 0.3 3 Methylparaben Preservative 0.2 2 Sodiumcitrate, dihydrate Buffer 1.0 10 Sucralose Sweetener 0.02 0.2 Poloxamer188 Solubilizer 1.0 10 Propylene Glycol Solubilizer 10.0 100 PurifiedWater Solvent 86.88 868.8

Unless otherwise noted, all components were added in thequantities/concentrations provided in Table 3 and all steps wereperformed at room temperature. Propylene glycol was added to a reactionvessel. Water was then added to the reaction vessel and the (first)mixture was stirred. Poloxamer 188 was added to the first mixture andstirred until there were no visible poloxamer 188 particles, forming asecond mixture. Methylparaben was then added to the second mixture andstirred until there were no visible methylparaben particles, forming athird mixture. Sodium citrate dihydrate was then added to the thirdmixture and stirred until there were no visible sodium citrate dihydrateparticles, forming a fourth mixture. Valsartan was slowly added to thefourth mixture and stirred until there were no visible valsartanparticles, forming a fifth mixture. Potassium sorbate was then added tothe fifth mixture and stirred until there were no potassium sorbateparticles, forming a sixth mixture. Sucralose and grape flavor wereadded to the sixth mixture and stirred until there were no sucralose orgrape flavor particles, forming a final mixture. Water was added to thefinal mixture, quantum satis to 1000 g and stirred.

Example 4. Stability Study of the Oral Liquid Composition Including 0.4%Valsartan (4 mg/mL) Stored in a Container Closure System Including 4 Oz.High Density Polyethylene (HDPE) Bottles

For purposes of conducting a stability study, 120 mL oral liquidcomposition #5 samples of Example 3 were packaged in a container closuresystem. For purposes of conducting a stability study, oral liquidcomposition #5 samples of Example 3 were packaged in a container closuresystem. Each container closure system, as shown in FIGS. 1A-1C, includeda 4 ounce (120 mL), Boston round white (colorant: white 11078 AMPACET),High Density Polyethylene (“HDPE”), (resin: MARLEX HHM 5502BN), bottlewith a 24 mm SECURX™ ribbed side pictorial top (resin: INEOS H20E-00),white closure (colorant: white 11343 AMPACET), with a foam liner (liner:SELIG SEALING 0.035″ C25 FSLE5-9) (see FIGS. 2A and 2B). Samples werestored upright under the following storage conditions: refrigeratedconditions (REF) (5° C.±3° C.); controlled room temperature conditions(25° C.±2° C. and 40%±5% RH); intermediate conditions (INT) (35° C.±2°C. and 65%±5% RH); and accelerated conditions (ACC) (40° C.±2° C. andnot more than (NMT) 25% RH). The samples were stored in a calibratedstability chamber. Samples of the oral liquid composition stored in thechamber were taken at set time intervals to assay for valsartan, pH,individual unspecified impurities, total impurities, total aerobicmicrobial count, and total yeast/mold count. Samples were analyzed usinga High Performance Liquid Chromatography (HPLC) system equipped with apump, autosampler, UV detector, and a suitable data acquisition system.The HPLC column used included packing L1 (C18), 5 rpm, 250 mm×4.6 mm.The HPLC parameters used included 230 nm detection, a flow rate of 1.5mL/min, an injection volume of 20 μL, run at ambient temperature, for arun time of 25 minutes using a mobile phase of acetonitrile, DI water,and glacial acetic acid (40:60:0.1).

Table 4 reports the stability data for the oral liquid compositionincluding, by weight, 0.4% valsartan (4 mg/mL), stored underrefrigerated conditions (5° C.±3° C.) and in the 4 oz. HDPE bottles ofthe container closure system, at 3, 6, 9, 12, 18, and 24 month timeintervals.

TABLE 4 Stability assay for the oral liquid composition containing, byweight, 0.4% valsartan, (4 mg/mL) tested under refrigerated conditions(5° C. ± 3° C.) and stored in 4 oz. HDPE bottles. Individual Unspec-Total Total ified Total Aerobic Yeast/ Valsar- Impuri- Impuri- MicrobialMold Time pH tan¹ (%) ties (%) ties (%) Count Count Initial 5.9 98.6<0.05 <0.05  <10 cfu²/g <10 cfu/g 3 mos. 5.9 99.9 <0.05 <0.05  NA³ NA 6mos. 5.9 98.6 <0.05 <0.05 NA NA 9 mos. 5.9 101.1 <0.05 <0.05 NA NA 12mos. 6.0 100.5 <0.05 <0.05 NA NA 18 mos. 6.0 99.1 <0.05 <0.05 NA NA 24mos. 6.0 100.0 <0.05 <0.05 <10 cfu/g <10 cfu/g ¹Assayed percentvalsartan present at specified time. ²cfu = colony forming units ³NA =not applicable

As indicated in Table 4, the oral liquid composition #5 of Example 3,originally including 0.4% valsartan (4 mg/mL), was stable for at least24 months when stored under refrigerated (REF) conditions in the 4 oz.HDPE bottles of the container closure system. The stability assay showedthat 100.0% of the original valsartan was retained in the oral liquidcomposition over the course of the refrigerated stability conditionsassay for 24 months.

Table 5 reports the stability data for the oral liquid composition #5,originally containing 0.4% valsartan (4 mg/mL), stored under standardconditions (25° C.±2° C. and 40%±5% RH) in 4 oz. HDPE bottles of thecontainer closure system, at 3, 6, 9, 12, 18, and 24 month timeintervals.

TABLE 5 Stability assay for oral liquid composition #5 tested understandard conditions (25° C. ± 2° C. and 40% ± 5% RH) and stored in 4 oz.HDPE bottles. Individual Unspec- Total Total ified Total Aerobic Yeast/Valsar- Impuri- Impuri- Microbial Mold Time pH tan¹ (%) ties (%) ties(%) Count Count Initial 5.9 98.6 <0.05 <0.05  <10 cfu²/g <10 cfu/g 3mos. 5.9 99.1 <0.05 <0.05  NA³ NA 6 mos. 5.9 98.7 <0.05 <0.05 NA NA 9mos. 6.0 100.9 0.05 0.1 NA NA 12 mos. 6.0 100.8 0.05 0.1 <10 cfu/g <10cfu/g 18 mos. 6.0 99.6 <0.05 <0.05 NA NA 24 mos. 6.0 99.6 0.1 0.1 <10cfu/g <10 cfu/g ¹Assayed percent valsartan present at specified time.²cfu = colony forming units ³NA = not applicable

As indicated in Table 5, the oral liquid composition #5, initiallyincluding 0.4% valsartan (4 mg/mL), was stable for at least 24 monthswhen stored under standard conditions of 25° C.±2° C. and 40%±5%relative humidity. The stability assay showed 99.6% of the originalvalsartan was retained in the oral liquid composition over the course ofthe standard stability conditions assay for 24 months and stored in 4oz. HDPE bottles of the container closure system.

Table 6 reports the stability data for the oral liquid composition #5,originally containing 0.4% valsartan (4 mg/mL), tested underintermediate conditions (35° C.±2° C. and 65%±5% RH) in 4 oz. HDPEbottles of the container closure system, at 3, 6, 9, 12, 18, and 24month time intervals.

TABLE 6 Stability assay for oral liquid composition #5 tested underintermediate conditions (35° C. ± 2° C. and 65% ± 5% RH) and stored in 4oz. HDPE bottles. Individual Unspec- Total Total ified Total AerobicYeast/ Valsar- Impuri- Impuri- Microbial Mold Time pH tan¹ (%) ties (%)ties (%) Count Count Initial 5.9 98.6 <0.05 <0.05  <10 cfu²/g <10 cfu/g3 mos. 5.9 99.5 <0.05 <0.05  NA³ NA 6 mos. 5.9 100.1 <0.05 <0.05 NA NA 9mos. 5.9 97.2 <0.05 <0.05 NA NA 12 mos. 5.9 99.2 <0.05 <0.05 NA NA 18mos. 6.0 100.0 0.07 0.1 NA NA 24 mos. 6.0 99.2 0.08 0.1 <10 cfu/g <10cfu/g ¹Assayed percent valsartan present at specified time. ²cfu =colony forming units ³NA = not applicable

As indicated in Table 6, the oral liquid composition #5, originallyincluding 0.4% valsartan (4 mg/mL), was stable for at least 24 monthswhen stored under intermediate conditions of 35° C.±2° C. and 65%±5%relative humidity in 4 oz. HDPE bottles of the container closure system.The stability assay showed 99.2% of the original valsartan was retainedin the oral liquid composition over the course of the intermediatestability conditions assay for 24 months.

Table 7 reports the stability data for the oral liquid composition #5,originally including 0.4% valsartan (4 mg/mL), tested under acceleratedconditions (40° C.±2° C. and NMT 25% RH) in 4 oz. HDPE bottles of thecontainer closure system, at 1, 2, 3, and 6 month time intervals.

TABLE 7 Stability assay for oral liquid composition #5 tested underaccelerated conditions (40° C. ± 2° C./NMT 25% RH) and stored in 4 oz.HDPE bottles. Individual Unspec- Total Total ified Total Aerobic Yeast/Valsar- Impuri- Impuri- Microbial Mold Time pH tan¹ (%) ties (%) ties(%) Count Count Initial 5.9 98.6 <0.05 <0.05  <10 cfu²/g <10 cfu/g 1mos. 5.9 99.5 <0.05 <0.05  NA³ NA 2 mos. 6.0 99.7 <0.05 <0.05 NA NA 3mos. 6.0 99.4 <0.05 <0.05 NA NA 6 mos. 5.9 99.1 <0.05 <0.05 <10 cfu/g<10 cfu/g ¹Assayed percent valsartan present at specified time. ²cfu =colony forming units ³NA = not applicable

As indicated in Table 7, the oral liquid composition #5, originallyincluding 0.4% valsartan (4 mg/mL), was stable for at least 6 monthswhen stored under accelerated conditions of 40° C.±2° C. and NMT 25%relative humidity in 4 oz. HDPE bottles of the container closure system.The stability assay showed 99.1% of the original valsartan was retainedin the oral liquid composition over the course of the acceleratedstability conditions assay for 6 months.

Example 5. Stability Study of the Oral Liquid Composition Including 0.4%Valsartan (4 mg/mL) Stored in a Container Closure System Including 16Ounce (473 mL) High Density Polyethylene (HDPE) Bottles

For purposes of conducting a stability study, the oral liquidcomposition #5 samples of Example 3, originally containing, by weight ofthe composition, 0.4% valsartan (4 mg/mL), were packaged in a containerclosure system and stored under specified conditions. Each containerclosure system, as shown in FIGS. 3A-3C, included a 16 ounce (473 mL),rectangular white (Colorant: White 11078 AMPACET), HDPE (Resin: MARLEXHHM 5502BN) bottle with a 28/480 mm continuous thread ribbed side smoothtop (Resin: INEOS H20E-00) white closure (Colorant: White 11343AMPACET), with a foam liner (SELIG SEALING 0.035″ C25 FSLE5-9), (seeFIGS. 4A and 4B). Samples were stored upright under the followingstorage conditions: refrigerated conditions (REF) (5° C.±3° C.);controlled room temperature conditions (25° C.±2° C. and 40%±5% RH);intermediate conditions (INT) (35° C.±2° C./65%±5% RH); and acceleratedconditions (ACC) (40° C.±2° C. and not more than (NMT) 25% RH). Thestability samples were stored in a calibrated stability chamber. Samplesof the stored oral liquid composition were taken at set time intervalsto assay for valsartan, pH, individual unspecified impurities, totalimpurities, total aerobic microbial count, and total yeast/mold count.Samples were analyzed using a High Performance Liquid Chromatography(HPLC) system equipped with a pump, autosampler, UV detector, and asuitable data acquisition system. The HPLC column used included packingL1 (C18), 5 m, 250 mm×4.6 mm. The HPLC parameters used included 230 nmdetection, a flow rate of 1.5 mL/min, an injection volume of 20 μL, runat ambient temperature, for a run time of 25 minutes using a mobilephase of acetonitrile, DI water, and glacial acetic acid (40:60:0.1).

Table 8 reports the stability data for the oral liquid composition #5containing, by weight, 0.4% valsartan (4 mg/mL), tested underrefrigerated conditions (5° C.±3° C.) stored in 16 oz. HDPE bottles ofthe container closure system, at 3, 6, 9, 12, 18, and 24 month timeintervals.

TABLE 8 Stability assay for oral liquid composition #5 tested underrefrigerated conditions (5° C. ± 3° C.) and stored in 16 oz. HDPEbottles. Individual Unspec- Total Total ified Total Aerobic Yeast/Valsar- Impuri- Impuri- Microbial Mold Time pH tan¹ (%) ties (%) ties(%) Count Count Initial 5.9 99.4 <0.05 <0.05  <10 cfu²/g <10 cfu/g 3mos. 5.9 99.1 <0.05 <0.05  NA³ NA 6 mos. 5.9 99.5 <0.05 <0.05 NA NA 9mos. 5.9 99.6 <0.05 <0.05 NA NA 12 mos. 6.0 100.1 <0.05 <0.05 NA NA 18mos. 6.0 98.9 <0.05 <0.05 NA NA 24 mos. 6.0 99.8 <0.05 <0.05 <10 cfu/g<10 cfu/g ¹Assayed percent valsartan present at specified time. ²cfu =colony forming units ³NA = not applicable

As shown in Table 8 above, the oral liquid composition #5, whichoriginally included 0.4% valsartan (4 mg/mL), was stable for at least 24months when stored under refrigerated conditions (5° C.±3° C.) in 16 oz.HDPE bottles of the container closure system. The stability assay showed99.8% of the original valsartan was retained in the oral liquidcomposition over the course of the refrigerated stability conditionsassay for 24 months while stored in 16 oz. HDPE bottles of the containerclosure system.

Table 9 reports the stability data for the oral liquid composition #5containing, by weight, 0.4% valsartan (4 mg/mL), stored under standardconditions (25° C.±3° C. and 40%±5% RH) in 16 oz. HDPE bottles of thecontainer closure system, at 3, 6, 9, 12, 18, and 24 month timeintervals.

TABLE 9 Stability assay for oral liquid composition #5 tested understandard conditions (25° C. ± 2° C./40% ± 5% RH) and stored in 16 oz.HDPE bottles. Individual Unspec- Total Total ified Total Aerobic Yeast/Valsar- Impuri- Impuri- Microbial Mold Time pH tan¹ (%) ties (%) ties(%) Count Count Initial 5.9 99.4 <0.05 <0.05  <10 cfu²/g <10 cfu/g 3mos. 5.9 99.5 <0.05 <0.05  NA³ NA 6 mos. 5.9 99.4 <0.05 <0.05 NA NA 9mos. 6.0 99.7 <0.05 <0.05 NA NA 12 mos. 6.0 99.7 0.05 0.1 <10 cfu/g <10cfu/g 18 mos. 6.0 99.0 <0.05 <0.05 NA NA 24 mos. 6.0 100.4 0.11 0.1 <10cfu/g <10 cfu/g ¹Assayed percent valsartan present at specified time.²cfu = colony forming units ³NA = not applicable

As indicated in Table 9, the oral liquid composition #5, of Example 3,originally including, by weight, 0.4% valsartan (4 mg/mL), was stablefor at least 24 months when stored under standard conditions of 25°C.±2° C. and 40%±5% relative humidity in 16 oz. HDPE bottles of thecontainer closure system. The stability assay showed 100% of theoriginal valsartan was retained in the oral liquid composition over thecourse of the standard stability conditions assay for 24 months whilestored in 16 oz. HDPE bottles of the container closure system.

Table 10 reports the stability data for the oral liquid composition #5including, by weight, 0.4% valsartan (4 mg/mL), stored underintermediate conditions (35° C.±2° C. and 65%±5% RH) in 16 oz. HDPEbottles of the container closure system, at 3, 6, 9, 12, 18, and 24month time intervals.

TABLE 10 Stability assay for oral liquid composition #5 tested underintermediate conditions (35° C. ± 2° C. and 65% ± 5% RH) and stored in16 oz. HDPE bottles. Individual Unspec- Total Total Total ified Impuri-Aerobic Yeast/ Valsar- Impuri- ties Microbial Mold Time pH tan¹ (%) ties(%) (%) Count Count Initial 5.9 99.4 <0.05 <0.05  <10 cfu²/g <10 cfu/g 3mos. 5.9 99.5 <0.05 <0.05  NA³ NA 6 mos. 5.9 98.5 <0.05 <0.05 NA NA 9mos. 5.9 97.8 <0.05 <0.05 NA NA 12 mos. 5.9 99.0 <0.05 <0.05 NA NA 18mos. 6.0 100.1 0.07 0.1 NA NA 24 mos. 6.0 99.3 0.09 0.1 <10 cfu/g <10cfu/g ¹Assayed percent valsartan present at specified time. ²cfu =colony forming units ³NA = not applicable

As indicated in Table 10, the oral liquid composition #5, whichoriginally included 0.4% valsartan (4 mg/mL), was stable for at least 24months when stored under intermediate conditions of 35° C.±2° C. and65%±5% relative humidity in 16 oz. HDPE bottles of the container closuresystem. The stability assay showed 99.3% of the original valsartan wasretained in the oral liquid composition over the course of theintermediate stability conditions assay for 24 months while stored in 16oz. HDPE bottles of the container closure system.

Table 11 reports the stability data for the oral liquid composition #5containing, by weight, 0.4% valsartan (4 mg/mL), stored underaccelerated conditions (40° C.±2° C./NMT 25% RH) in 16 oz. HDPE bottlesof the container closure system, at 1, 2, 3, and 6 month time intervals.

TABLE 11 Stability assay for oral liquid composition #5 tested underaccelerated conditions (40° C. ± 2° C./NMT 25% RH) and stored in 16 oz.HDPE bottles. Individual Unspec- Total Total ified Total Aerobic Yeast/Valsar- Impuri- Impuri- Microbial Mold Time pH tan¹ (%) ties (%) ties(%) Count Count Initial 5.9 99.4 <0.05 <0.05  <10 cfu²/g <10 cfu/g 1mos. 5.9 97.8 0.11 0.1  NA³ NA 2 mos. 6.0 99.2 <0.05 <0.05 NA NA 3 mos.6.0 99.7 <0.05 <0.05 NA NA 6 mos. 5.9 98.8 <0.05 <0.05 <10 cfu/g <10cfu/g ¹Assayed percent valsartan present at specified time. ²cfu =colony forming units ³NA = not applicable

As shown in Table 11, the oral liquid composition #5, of Example 3,originally including 0.4% valsartan (4 mg/mL), was stable for at least 6months when stored under accelerated conditions of 40° C.±2° C. with nomore than (NMT) 25% relative humidity in 16 oz. HDPE bottles of thecontainer closure system. The stability assay showed 98.8% of theoriginal valsartan was retained in the oral liquid composition over thecourse of the accelerated stability conditions assay for 6 months whilestored in 16 oz. HDPE bottles of the container closure system.

Example 6. Stability Study of the Oral Liquid Composition Containing0.4% (4 Mg/mL) Valsartan Stored in 25 mL Unit Dose Cups

For purposes of conducting a stability study, the oral liquidcomposition #5 samples of Example 3 (20 mL), originally containing 0.4%(4 mg/mL) valsartan, were packaged in a container closure system. Eachcontainer closure system, as shown in FIG. 5, included a 25 mL unit dosecup made of HDPE (Resin: HDPE H5618; Colorant: Blue PolypropyleneCPP2347) with a foil closure of 2.125″ lidstock (Material: Lidding,0.0032 PET, foil). Samples were stored in the container closure systemupright under the following storage conditions: refrigerated conditions(REF) (5° C.±3° C.); controlled room temperature conditions (25° C.±2°C. and 40%±5%); intermediate conditions (INT) (35° C.±2° C. and 65%±5%RH); and accelerated conditions (ACC) (40° C.±2° C. and not more than(NMT) 25% RH).

The stability samples were stored in a calibrated stability chamber.Samples of the oral liquid composition were taken at set time intervalsto assay for valsartan, pH, individual unspecified impurities, totalimpurities, total aerobic microbial count, and total yeast/mold count.Samples were analyzed using a High Performance Liquid Chromatography(HPLC) system equipped with a pump, autosampler, UV detector, and asuitable data acquisition system. The HPLC column used included packingL1 (C18), 5 m, 250 mm×4.6 mm. The HPLC parameters used included 230 nmdetection, a flow rate of 1.5 mL/min, an injection volume of 20 μL, runat ambient temperature, for a run time of 25 minutes using a mobilephase of acetonitrile, DI water, and glacial acetic acid (40:60:0.1).

Table 12 reports the stability data for the oral liquid compositioncontaining, by weight, 0.4% valsartan (4 mg/mL), stored underrefrigerated conditions (5° C.±3° C.) in 25 mL Unit Dose Cups, at 3, 6,9, 12, 18, and 24 month time intervals.

TABLE 12 Stability assay for the oral liquid composition containing, byweight, 0.4% valsartan, (4 mg/mL) tested under refrigerated conditions(5° C. ± 3° C.) and stored in a 25 mL Unit Dose Cup. Individual Unspec-Total Total ified Total Aerobic Yeast/ Valsar- Impuri- Impuri- MicrobialMold Time pH tan¹ (%) ties (%) ties (%) Count Count Initial 5.9 99.8<0.05 <0.05  <10 cfu²/g <10 cfu/g 3 mos. 5.9 99.2 0.11 0.1  NA³ NA 6mos. 5.9 99.7 <0.05 <0.05 NA NA 9 mos. 5.9 99.6 <0.05 <0.05 NA NA 12mos. 6.0 99.0 <0.05 <0.05 NA NA 18 mos. 6.0 99.0 <0.05 <0.05 NA NA 24mos. 6.0 99.9 <0.05 <0.05 <10 cfu/g <10 cfu/g ¹Assayed percent valsartanpresent at specified time. ²cfu = colony forming units ³NA = notapplicable

As indicated in Table 12, the oral liquid composition #5, originallyincluding 0.4% valsartan (4 mg/mL), was stable for at least 24 monthswhen stored under refrigerated (REF) conditions of 5° C.±3° C. relativehumidity in 25 mL Unit Dose Cups. The stability assay showed 99.9% ofthe original valsartan was retained in the oral liquid composition overthe course of the refrigerated stability conditions assay for 24 monthswhile stored in 25 mL Unit Dose Cups.

Table 13 reports the stability data for the oral liquid compositioncontaining, by weight, 0.4% valsartan (4 mg/mL), stored under standardconditions (25° C.±2° C. and 40%±5% RH) in 25 mL Unit Dose Cup, at 3, 6,9, 12, 18, and 24 month time intervals.

TABLE 13 Stability assay for the oral liquid composition containing, byweight, 0.4% valsartan, (4 mg/mL) tested under standard conditions (25°C. ± 2° C./40% ± 5% RH) and stored in 25 mL Unit Dose Cups. IndividualUnspec- Total Total ified Total Aerobic Yeast/ Valsar- Impuri- Impuri-Microbial Mold Time pH tan¹ (%) ties (%) ties (%) Count Count Initial5.9 99.8 <0.05 <0.05  <10 cfu²/g <10 cfu/g 3 mos. 5.9 98.1 <0.05 <0.05 NA³ NA 6 mos. 5.9 100.9 <0.05 <0.05 NA NA 9 mos. 6.0 99.7 <0.05 <0.05NA NA 12 mos. 6.0 99.7 <0.05 <0.05 <10 cfu/g <10 cfu/g 18 mos. 6.0 99.00.07 0.1 NA NA 24 mos. 6.0 99.4 0.1 0.1 <10 cfu/g <10 cfu/g ¹Assayedpercent valsartan present at specified time. ²cfu = colony forming units³NA = not applicable

As indicated in Table 13, the oral liquid composition #5, originallyincluding 0.4% valsartan (4 mg/mL), was stable for at least 24 monthswhen stored under standard conditions (25° C.±2° C. and 40%±5% RH) in 25mL Unit Dose Cups. The stability assay showed 99.4% of the originalvalsartan was retained in the oral liquid composition over the course ofthe standard stability conditions assay for 24 months.

Table 14 reports the stability data for the oral liquid composition #5containing, by weight, 0.4% valsartan (4 mg/mL), stored underintermediate conditions (35° C.±2° C. and 65%±5% RH) in 25 mL Unit DoseCups, at 3, 6, 9, 12, 18, and 24 month time intervals.

TABLE 14 Stability assay for the oral liquid composition containing, byweight, 0.4% valsartan, (4 mg/mL) tested under intermediate conditions(35° C. ± 2° C./65% ± 5% RH) and stored in 25 mL Unit Dose Cups.Individual Unspec- Total Total ified Total Aerobic Yeast/ Valsar-Impuri- Impuri- Microbial Mold Time pH tan¹ (%) ties (%) ties (%) CountCount Initial 5.9 99.8 <0.05 <0.05  <10 cfu²/g <10 cfu/g 3 mos. 5.9 97.8<0.05 <0.05  NA³ NA 6 mos. 5.9 98.1 <0.05 <0.05 NA NA 9 mos. 5.9 99.9<0.05 <0.05 NA NA 12 mos. 5.9 100.5 <0.05 <0.05 NA NA 18 mos. 6.0 100.80.06 0.1 NA NA 24 mos. 6.0 98.7 0.07 0.1 <10 cfu/g <10 cfu/g ¹Assayedpercent valsartan present at specified time. ²cfu = colony forming units³NA = not applicable

As shown in Table 14 above, the oral liquid composition #5, whichoriginally included 0.4% valsartan (4 mg/mL), was stable for at least 24months when stored under intermediate conditions (35° C.±2° C./65%±5%RH) in 25 mL Unit Dose Cups. The stability assay showed 98.7% of theoriginal valsartan was retained in the oral liquid composition over thecourse of the intermediate stability conditions assay for 24 months inthe 25 mL Unit Dose Cups.

Table 15 reports the stability data for the oral liquid compositioncontaining, by weight, 0.4% valsartan (4 mg/mL), stored underaccelerated conditions (40° C.±2° C. and NMT 25% RH) in 25 mL Unit DoseCups, at 1, 2, 3, and 6 month time intervals.

TABLE 15 Stability assay for the oral liquid composition containing, byweight, 0.4% valsartan, (4 mg/mL) tested under accelerated conditions(40° C. ± 2° C./NMT 25% RH) and stored in 25 mL Unit Dose Cups.Individual Unspec- Total Total Valsar- ified Total Aerobic Yeast/ tan¹Impuri- Impuri- Microbial Mold Time pH (%) ties (%) ties (%) Count CountInitial 5.9 99.8 <0.05 <0.05  <10 cfu²/g <10 cfu/g 1 mos. 5.9 99.4 <0.05<0.05  NA³ NA 2 mos. 6.0 99.4 <0.05 <0.05 NA NA 3 mos. 6.0 99.5 <0.05<0.05 NA NA 6 mos. 5.9 100.3 <0.05 <0.05 <10 cfu/g <10 cfu/g ¹Assayedpercent valsartan present at specified time. ²cfu = colony forming units³NA = not applicable

As indicated in Table 15, the oral liquid composition #5, whichoriginally included 0.4% valsartan (4 mg/mL), was stable for at least 6months stored under accelerated conditions (40° C.±2° C. and NMT 25% RH)in 25 mL Unit Dose Cups. The stability assay showed 100% of the originalvalsartan was retained in the oral liquid composition over the course ofthe accelerated stability conditions assay for 6 months and stored inthe 25 mL Unit Dose Cups.

Example 7. A Comparative Bioequivalence Study of an Oral LiquidComposition Including Valsartan (4 mg/mL, Total of 320 mg) with aReference Product Tablet Including Valsartan (320 mg)

A bioequivalence study was conducted on healthy, adult, human subjectsunder fasting conditions to assess comparative bioavailability of asingle oral dose (80 mL) of an oral liquid composition including 4 mg/mLvalsartan (total 320 mg) with a reference product tablet including 320mg of valsartan.

A further objective of the bioequivalence study was to assess the safetyand tolerability of a single dose (80 mL) of an oral liquid compositionincluding valsartan (40 mg/mL, total of 320 mg valsartan) administeredto healthy, adult, human subjects under fasting conditions.

Table 16 lists the ingredients combined to provide the oral liquidcomposition including valsartan administered to subjects in thebioequivalence study of this Example 7.

TABLE 16 Composition of the oral liquid composition including valsartan(4 mg/mL) administered in the bioequivalence study of Example 7. Amount(mg)/ Weight Batch Ingredient dose (4 mg/mL) Percent Size (kg) Valsartan4.0 0.40 0.80 Potassium Sorbate 2.0 0.20 0.40 Methylparaben 2.0 0.200.40 Grape Flavor 3.0 0.30 0.60 Poloxamer 10.0 1.0 2.0 Sodium CitrateDihydrate 10.0 1.0 2.0 Sucralose 0.20 0.02 0.04 Propylene Glycol 10010.0 20.0 Purified Water 868.8 86.9 QS to 200 Liters TOTAL 1000.0 100.0200 Liters

The study was conducted with 66 healthy, adult male subjects in an agerange of 18 to 45 years with a body-mass index of at least 18.5 kg/m²and not more than 24.9 kg/m², and with a body weight not less than 50kg. Table 17 reports the demographics of the subjects participating inthe bioequivalence study of Example 7.

TABLE 17 Demographic profile of the participants completing thebioequivalence study of Example 7. Oral Liquid Composition includingValsartan Valsartan Tablet (320 mg) (320 mg) Age Mean ± SD 28.15 ± 6.1728.15 ± 6.17 Range  18-43  18-43 Age Group 18-40   60 (90.91%)   60(90.91%) 41-64  06 (9.09%)  06 (9.09%) Sex Male 66 (100%) 66 (100%)Female — — Race Asian 66 (100%) 66 (100%) BMI (Kg/m²) Mean ± SD 22.87 ±2.84 22.87 ± 2.84 Range 18.57 to 24.88 18.57 to 24.88 Height (m) Mean ±SD  1.67 ± 0.05  1.67 ± 0.05 Range 1.51 to 1.77 1.51 to 1.77 Weight (kg)Mean ± SD 63.63 ± 7.23 63.63 ± 7.23 Range 50.40 to 77.90 50.40 to 77.90

Treatment period one of the bioequivalence study of Example 7 includedadministering a single dose of 80 mL of the oral liquid compositionincluding 4 mg/mL valsartan (a total of 320 mg valsartan) to each of thestudy subjects as per a randomization schedule under fasting conditionsovernight (no food for at least 10 hours). Treatment period two of thestudy included administering a single 320 mg tablet of valsartan to thesame subjects who had participated in the first treatment period as pera randomization schedule, also under fasting conditions overnight (nofood for at least 10 hours). The total duration of the study was elevendays with a washout period of seven days between the first and secondtreatment periods. The single dose of medication was administered to thesubjects in a sitting posture with 240 mL water. Standard meals of2200-2400 kcal. were provided to subjects at 4, 8, and 13 hourspost-dosing on Day 1. Drinking of water was restricted one hour beforeand one hour after administration of the medication, except for the 240mL of water given at the time of administration of the medication.

Twenty five blood samples (1×5 ml) were collected in pre-labelled K2EDTA vacutainers from each subject following administration. Singlevenous blood samples were withdrawn at pre-dose (t=0.00) and at 0.33,0.66, 1.00, 1.33, 1.66, 2.00, 2.33, 2.66, 3.00, 3.33, 3.66, 4.00, 4.33,4.66, 5.00, 5.50, 6.00, 7.00, 8.00, 10.00, 12.00, 16.00, 24.00 and 48.00hours post-dose. The cannulation was carried out before pre-dose samplecollection and was maintained until the 12.00 hour sample. After the12.00 hour sample was withdrawn, the cannula was removed and samplecollection was completed by direct venipuncture. Pre-dose blood sampleswere collected at a phlebotomy station, and post-dose blood samples werecollected at bedside from 0.33 hrs to 8.00 hrs. Following the collectionat 8.00 hours, blood samples were collected at the phlebotomy station.

Valsartan was estimated in plasma using a High Performance LiquidChromatography Mass Spectrometric Method in Positive Ion Mode for theestimation of valsartan in human plasma using Valsartan d9 as aninternal standard. Sample preparation was accomplished by Solid-Phaseextraction technique. The reconstituted samples were chromatographed onKromasil 100-5-C18, 100×4.6 mm, 5 μm column (Manufacturer: AkzoNovel,Amsterdam, Netherlands) using a mobile phase consisting of 0.1% formicacid: methanol (20:30, v/v). Pharmacokinetic parameters of C_(max),AUC_(last), AUC_(inf), T_(max), t_(1/2), K_(el), and AUC_% Extrap_Obswere estimated for valsartan by using Phoenix WinNonlin 6.3. Table 18reports the pharmacokinetic parameters determined in the study ofExample 7.

TABLE 18 Pharmacokinetic parameters determined in subjects participatingin the bioequivalence study of the oral liquid composition includingvalsartan (4 mg/mL, 320 mg valsartan) and valsartan tablet (320 mg) ofExample 7. Oral Liquid Pharmacokinetic Composition (4 mg/mL ValsartanParameter valsartan, 320 mg) tablet (320 mg) T_(max) (hr) 1.00(0.66-2.66) 4.00 (1.33-5.50) C_(max) (ng/mL) 11498 (±3216) 6606 (±3220)AUC_(last) (ng · hr/mL) 52176 (±18298) 43580 (±21528) AUC_(inf) (ng ·hr/mL) 53646 (±18484) 45001 (±21857) T_(1/2) (hr) 5.71 (±1.72) 5.69(±2.61) K_(el) (hr⁻¹) 0.128 (±0.0258) 0.134 (±0.032) AUC_% Extrap obs2.89 (±1.81) 3.55 (±2.45)

The 90% confidence intervals for the log transformed C_(max),AUC_(last), and AUC_(inf) of valsartan are reported in Table 19. The 90%confidence intervals of the ratio (liquid/tablet) of the least squaresmeans for C_(max), AUC_(last), and AUC_(inf) of valsartan form the basisfor concluding the equivalence of the oral liquid composition includingvalsartan and the valsartan tablet. The criteria applied to concludethat the two “treatments” (administration of the oral liquid compositionand administration of the valsartan tablet) are “bio-equivalent” is thatthe point estimate of the ratio and the confidence intervals must beentirely included in the range of 80.00% to 125.00% for C_(max),AUC_(last), and AUC_(inf) for the log-transformed data.

TABLE 19 The 90% confidence intervals for the log transformed C_(max),AUC_(last), and AUC_(inf) pharmacokinetic parameters for the oral liquidcomposition including valsartan (4 mg/mL valsartan, total 320 mgvalsartan) and for the valsartan tablets (320 mg valsartan).Pharmacokinetic 90% C.I. for log transformed data (%) ParametersValsartan C_(max) (ng/mL) 170 to 205 AUC_(last) (ng · hr/mL) 115 to 137AUC_(inf) (ng · hr/mL) 114 to 136

As shown in Table 19, the 90% confidence intervals for the logtransformed C_(max), AUC_(last), and AUC_(inf) of valsartan are notwithin the 80% to 125% acceptance criteria. For example, the 90%confidence interval for the C_(max) of Example 7 ranges from 170% to205%, which is outside of the 80% to 125% acceptance range. Thus, theconclusion reached from the study of Example 7 is that the oral liquidcomposition including valsartan (4 mg/mL) is not bioequivalent to thevalsartan 320 mg tablets when administered to healthy, adult, malesubjects under fasting conditions. Additionally, in general, the safetyprofiles of the oral liquid composition including valsartan and thevalsartan 320 mg tablets were found to be similar. During the Example 7study, there were no reports of death or serious or unexpected adverseevents.

Example 8. A Bioavailability Study of an Oral Liquid CompositionIncluding Valsartan (4 mg/mL, a Total of 320 mg Valsartan) FollowingAdministration to Human Subjects Under Fasting and Fed Conditions

Objectives for the bioavailability study of Example 8 were to determinethe effect of food on the pharmacokinetics of the oral liquidcomposition including valsartan (4 mg/mL, a total of 320 mg valsartan)and to determine the safety and tolerability of the oral liquidcomposition on subjects administered the composition.

More specifically, the study of this Example 8 was conducted to comparepharmacokinetic parameters resulting from administering an oral liquidcomposition including valsartan (4 mg/mL, total of 320 mg valsartan) tohealthy subjects under fed and fasting conditions.

A total of eighteen healthy adult human subjects participated in Example8. Table 20 reports the demographics of the participating subjects.

TABLE 20 Demographic profile of the participants completing thebioavailability study of Example 8. Treatment Conditions Category FastFed Age Mean ± SD 30.9 ± 4.09 30.9 ± 4.09 Range 24-39 24-39 Median 31  31   N 18   18   Age Groups 18-40 18 (100%) 18 (100%) Gender Male 18(100%) 18 (100%) Race Asian 18 (100%) 18 (100%) Height (meter) Mean ± SD1.67 ± 0.07 1.67 ± 0.07 Range 1.53-1.80 1.53-1.80 Median  1.68  1.68Weight (kg) Mean ± SD 65.2 ± 7.34 65.2 ± 7.34 Range 50.6-79.0 50.6-79.0Median 66.1 66.1 BMI (kg/m²) Mean ± SD 23.4 ± 1.87 23.4 ± 1.87 Range18.6-24.9 18.6-24.9 Median 23.9 23.9

During part I of the study of Example 8, a randomized schedule initiallyselected nine subjects for administration of 80 mL of the oral liquidcomposition (including 320 mg valsartan) under fasting conditions andnine subjects for administration of the composition under fedconditions. Following the collection and analysis of blood samples fromthe subjects, the subjects were given a washout period of seven days.After the washout period, the subjects then participated in part II ofthe study of Example 8. In part II, the subjects were again administeredthe oral liquid composition including valsartan, but were given thecomposition under fed conditions if the subject had been fasting in partI, and under fasting conditions if the subject had been fed in part I.

A single dose of 80 mL of oral liquid composition including valsartan (4mg/mL, a total of 320 mg valsartan) was administered to the subjects ina sitting posture with 240 mL water. The subjects were instructed toremain in a sitting posture for two hours following the administrationof the composition.

Subjects that were fasting were administered the oral liquid compositionincluding valsartan after at least 10 hours of overnight fasting.Following administration of the oral liquid composition includingvalsartan (4 mg/mL, a total of 320 mg valsartan), each fasting subjectwas restricted from eating for four hours. After the four-hour period,each fasting subject was provided standard meals comprising 2200-2400kcal. at 4.00, 8.00, and 13.00 hours post dosing.

Subjects that were administered the oral liquid composition includingvalsartan under fed conditions initially fasted overnight for at least10 hours and then were served a standard non-vegetarian, high-calorie,high-fat, breakfast comprising 800-1000 kcal. The subjects were asked tocomplete eating the breakfast within 30 minutes followed byadministration of the oral liquid composition including valsartan (4mg/mL, a total of 320 mg valsartan). After the breakfast andadministration of the composition, food was restricted for four hoursfollowed by standard meals comprising 1700-1900 kcal at 4.00, 8.00, and13.00 hours post dosing. Other than the 240 mL of water given during theadministration of the oral liquid composition, drinking water wasrestricted for one hour before and one hour after administration of theoral liquid composition including valsartan (4 mg/mL, 320 mg valsartan).

Blood samples (1×5 mL) were collected from each of the subjects usingthe method and schedule as described in Example 7. Valsartan wasestimated in plasma using a High Performance Liquid Chromatography MassSpectrometric Method in Positive Ion Mode for the estimation ofvalsartan in human plasma using Valsartan d9 as an internal standard.Sample preparation was accomplished by Solid-Phase extraction technique.The reconstituted samples were chromatographed on Kromasil 100-5-C18,100×4.6 mm, 5 μm column (Make: AkzoNovel) using a mobile phaseconsisting of 0.1% formic acid: methanol (20:30, v/v). Pharmacokineticparameters of C_(max), AUC_(last), AUC_(inf), T_(max), t_(1/2), K_(el),and AUC_% Extrap_Obs were estimated for valsartan using PhoenixWinNonlin 6.3.

FIG. 6 shows a linear plot of the valsartan mean plasma concentrationversus time post administration of the oral liquid composition includingvalsartan (4 mg/mL, a total of 320 mg valsartan) in healthy, adultsubjects under the fed and fasting conditions of Example 8. Table 21reports the pharmacokinetic parameters determined from the blood plasmaof the subjects participating in the study of Example 8.

TABLE 21 Pharmacokinetic parameters determined in subjects participatingin the study of the oral liquid composition including valsartan (4mg/mL, 320 mg valsartan) as administered to subjects under both fed andfasting conditions. Summary of Valsartan Pharmacokinetic ResultsT_(max)* C_(max) AUC_(0-t) AUC_(0-∞) K_(el) t_(1/2) AUC_% Parameter (hr)(ng/mL) (ng · hr/mL) (ng · hr/mL) (1/hr) (hr) Extrap_Obs FastUntransformed Mean 1.00 11748 573988 591538 0.1158 6.26 3.03 Log - —9.34 10.9 10.9 — — — Transformed Least Square Mean Geometric Least —11402 56138 57895 — — — Square Mean Fed Untransformed Mean 2.17 650553206 55049 0.118  6.94 3.51 Log- — 8.76 10.8 10.9 — — — TransformedLeast Square Mean Geometric Least — 6398 51708 53601 — — — Square MeanFast/Fed Ratio (%) — 178 109 108 — — — 90% CI — 159-199 99.9-11899.9-117 — — — Intra-Subject — 19.5 14.4 13.4 — — — Variability (%)Power (%) — 94.8 99.5 99.8 — — —

FIG. 7 shows a semi-log plot of the mean plasma valsartan concentrationversus time post administration of the oral liquid composition includingvalsartan (4 mg/mL, a total of 320 mg valsartan) in healthy, adultsubjects under the fed and fasting conditions of Example 8. A summary ofthe pharmacokinetic parameters including the mean values and 90%confidence standard deviation of the mean values is provided in Table22.

TABLE 22 Summary of the pharmacokinetic parameters determined insubjects administered the oral liquid composition including valsartan (4mg/mL, 320 mg valsartan) under both fed and fasting conditions.Pharmacokinetic Valsartan Mean (±S.D.) Parameters Fast Fed T_(max) (hr)*1.00 (0.66-2.00) 2.17 (1.33-4.66) C_(max) (ng/mL) 11748 (±3023.26456)6505 (±1226) AUC_(0-t) 57398 (±12883) 53205 (±13339) (ng · hr/mL)AUC_(0-∞) 59153 (±13121) 55049 (±13232.50184) (ng · hr/mL) t_(1/2) (hr)6.26 (±1.4629) 6.94 (±4.0087) k_(el) (1/hr) 0.115 (±0.021) 0.118(±0.038) AUC_% 3.03 (±1.35) 3.51 (±1.87) Extrap obs *Median (Min.-Max.)

To determine whether the oral liquid composition including valsartan (4mg/mL, a total of 320 mg valsartan) was bioequivalent under both fastingand fed conditions, a ratio of the geometric least square mean and 90%confidence intervals for the log-transformed data was calculated. Table23 reports the results of the bioequivalence criteria for theadministration of the oral liquid composition including valsartan (4mg/mL, a total of 320 mg of valsartan) under fast and fed conditions.

TABLE 23 Summary of the 90% confidence interval bioequivalence criteriafor the administration of the oral liquid composition includingvalsartan (4 mg/mL, a total of 320 mg of valsartan) under fast and fedconditions. Geometric Least Fast/Fed 90% Squares Mean Ratio ConfidenceParameters Fast Fed (%) Interval C_(max) (ng/mL) 11402 6398 178  159-199AUC_(0-t) (ng*hr/mL) 56138 51708 109 99.9-118 AUC_(0-∞) (ng*hr/mL) 5789553601 108 99.9-117

The criteria applied to conclude that the oral liquid compositionincluding valsartan administered to healthy, adult male subjects underfed conditions is “bio-equivalent” to the oral liquid compositionincluding valsartan administered to healthy, adult male subjects underfasting conditions is that the point estimate of the ratio and theconfidence intervals must be entirely included in the range of 80.00% to125.00% for C_(max), AUC_(last), and AUC_(inf) for the log-transformeddata. As shown in Table 23, the 90% confidence intervals for the logtransformed C_(max), AUC_(last), and AUC_(inf), of valsartan are not allwithin the 80% to 125% acceptance criteria. For example, the 90%confidence interval for the C_(max) of Example 8 ranges from 159% to199%, which is entirely outside of the 80% to 125% acceptance range.Thus, the conclusion from the study of Example 8 is that the oral liquidcomposition including valsartan (4 mg/mL) administered to healthy, adultmale subjects under fasting conditions is not bioequivalent to the oralliquid composition including valsartan (4 mg/mL) administered tohealthy, adult male subjects under fed conditions. In general, thesafety profile of the oral liquid composition including valsartan underboth fasting and fed conditions was found to be similar. Further, duringthe Example 8 study there were no reports of death or serious orunexpected adverse events.

The following numbered clauses are directed to various non-limitingexamples of compositions and methods according to the presentdisclosure:

1. An oral liquid composition comprising valsartan, or apharmaceutically acceptable salt or solvate thereof, whereinadministration of a 320 mg dose of the oral liquid composition to apatient provides an in vivo plasma profile having a valsartan C_(max)between about 8281 ng/mL and about 14713 ng/mL.

2. An oral liquid composition comprising valsartan, or apharmaceutically acceptable salt or solvate thereof, whereinadministration of a 320 mg dose of the oral liquid composition to apatient provides an in vivo plasma profile having a valsartan AUC_(inf)between about 35,162 ng*hr/mL and about 72,130 ng*hr/mL.

3. An oral liquid composition comprising valsartan, or apharmaceutically acceptable salt or solvate thereof, whereinadministration of a dose of the oral liquid composition to a patientprovides an in vivo plasma profile with a valsartan AUC_(inf) within arange of about 114% to about 136% of the valsartan AUC_(inf) resultingfrom administration of an oral tablet dosage form including the samedosage of valsartan to the patient.

4. A method comprising administering an oral liquid compositionincluding valsartan to a patient, wherein the method achieves avalsartan C_(max) in the patient ranging from about 8,281 ng/mL andabout 14,713 ng/mL.

5. A method comprising administering an oral liquid compositionincluding valsartan to a patient, wherein the method achieves avalsartan AUC_(inf) in the patient ranging from about 35,162 ng*hr/mLand about 72,130 ng*hr/mL.

6. A method of treating heart failure comprising administering to apatient in need thereof, regardless of whether the patient is underfasted or fed conditions, an oral liquid composition comprisingvalsartan, a preservative, and a sodium citrate dehydrate.

It will be understood that the present description illustrates thoseaspects of the invention relevant to a clear understanding of theinvention. Certain aspects that would be apparent to those of ordinaryskill in the art and that, therefore, would not facilitate a betterunderstanding of the invention have not been presented in order tosimplify the present description. Although only a limited number ofembodiments of the present invention are necessarily described herein,one of ordinary skill in the art will, upon considering the foregoingdescription, recognize that many modifications and variations of theinvention may be employed. All such variations and modifications of theinvention are intended to be covered by the foregoing description andthe following claims.

What is claimed is:
 1. An oral liquid solution comprising: 3.6 mg/mL to4.4 mg/mL valsartan or a pharmaceutically acceptable salt or solvatethereof; a buffering agent comprising a citrate salt; and water;provided that a pH of the oral liquid solution is 5.5 to 6.5 and theoral liquid solution is stable for at least 6 months when stored at atemperature ranging from 38° C. to 42° C. and not more than 25% relativehumidity; and provided that the valsartan or the pharmaceuticallyacceptable salt or solvate thereof is fully solubilized in the oralliquid solution.
 2. The oral liquid solution of claim 1, furthercomprising 2 mg/mL methylparaben.
 3. The oral liquid solution of claim1, further comprising 0.2 mg/mL sucralose.
 4. The oral liquid solutionof claim 1, wherein a mole ratio of citrate salt to valsartan is about3.7.1.
 5. The oral liquid solution of claim 1, further comprising asorbate salt.
 6. The oral liquid solution of claim 5, wherein thesorbate salt comprises potassium sorbate.
 7. The oral liquid solution ofclaim 6, wherein a mole ratio of potassium sorbate to valsartan is about1.5:1.
 8. The oral liquid solution of claim 1, wherein the pH of theoral liquid solution is 5.8 to 6.1.
 9. The oral liquid solution of claim1, wherein total impurities in the oral liquid solution are not morethan 0.4% w/w.
 10. An oral liquid solution comprising: 3.6 mg/mL to 4.4mg/mL valsartan or a pharmaceutically acceptable salt or solvatethereof; a buffering agent comprising a citrate salt, wherein a moleratio of citrate salt to valsartan is about 3:1 to about 4:1; and water;provided that a pH of the oral liquid solution is 5.8 to 6.1 and theoral liquid solution is stable for at least 6 months when stored at atemperature ranging from 38° C. to 42° C. and not more than 25% relativehumidity; and provided that the valsartan or the pharmaceuticallyacceptable salt or solvate thereof is fully solubilized in the oralliquid solution.
 11. The oral liquid solution of claim 10, wherein amole ratio of citrate salt to valsartan is about 3.7:1.
 12. The oralliquid solution of claim 10, further comprising a sorbate salt.
 13. Theoral liquid solution of claim 12, wherein the sorbate salt comprisespotassium sorbate.
 14. The oral liquid solution of claim 13, wherein amole ratio of potassium sorbate to valsartan is about 1.5:1.
 15. Amethod of treating hypertension comprising administering to a patient inneed thereof an oral liquid solution comprising: 3.6 mg/mL to 4.4 mg/mLvalsartan or a pharmaceutically acceptable salt or solvate thereof; abuffering agent comprising a citrate salt; and water; provided that a pHof the oral liquid solution is 5.5 to 6.5 and the oral liquid solutionis stable for at least 6 months when stored at a temperature rangingfrom 38° C. to 42° C. and not more than 25% relative humidity; andprovided that the valsartan or the pharmaceutically acceptable salt orsolvate thereof is fully solubilized in the oral liquid solution. 16.The method of claim 15, wherein in the oral liquid solution a mole ratioof citrate salt to valsartan is about 3.7:1.
 17. The method of claim 15,wherein the oral liquid solution further comprises a sorbate salt. 18.The method of claim 17, wherein the sorbate salt comprises potassiumsorbate.
 19. The method of claim 18, wherein a mole ratio of potassiumsorbate to valsartan is about 1.5:1.
 20. The method of claim 15, whereinthe pH of the oral liquid solution is 5.8 to 6.1.
 21. The method ofclaim 15, wherein the oral liquid solution comprises: 3.6 mg/mL to 4.4mg/mL valsartan or a pharmaceutically acceptable salt or solvatethereof; a buffering agent comprising a citrate salt, wherein a moleratio of citrate salt to valsartan is about 3:1 to about 4:1; and water;provided that a pH of the oral liquid solution is 5.8 to 6.1 and theoral liquid solution is stable for at least 6 months when stored at atemperature ranging from 38° C. to 42° C. and not more than 25% relativehumidity; and provided that the valsartan or the pharmaceuticallyacceptable salt or solvate thereof is fully solubilized in the oralliquid solution.
 22. The method of claim 21, wherein the oral liquidsolution further comprises a sorbate salt.
 23. The method of claim 22,wherein the sorbate salt comprises potassium sorbate.
 24. A method oftreating heart failure comprising administering to a patient in needthereof an oral liquid solution comprising: 3.6 mg/mL to 4.4 mg/mLvalsartan or a pharmaceutically acceptable salt or solvate thereof; abuffering agent comprising a citrate salt; and water; provided that a pHof the oral liquid solution is 5.5 to 6.5 and the oral liquid solutionis stable for at least 6 months when stored at a temperature rangingfrom 38° C. to 42° C. and not more than 25% relative humidity; andprovided that the valsartan or the pharmaceutically acceptable salt orsolvate thereof is fully solubilized in the oral liquid solution. 25.The method of claim 24, wherein in the oral liquid solution a mole ratioof citrate salt to valsartan is about 3.7:1.
 26. The method of claim 24,wherein the oral liquid solution further comprises a sorbate salt. 27.The method of claim 26, wherein the sorbate salt comprises potassiumsorbate.
 28. The method of claim 27, wherein a mole ratio of potassiumsorbate to valsartan is about 1.5:1.
 29. The method of claim 24, whereinthe pH of the oral liquid solution is 5.8 to 6.1.
 30. The method ofclaim 24, wherein the oral liquid solution comprises: 3.6 mg/mL to 4.4mg/mL valsartan or a pharmaceutically acceptable salt or solvatethereof; a buffering agent comprising a citrate salt, wherein a moleratio of citrate salt to valsartan is about 3:1 to about 4:1; and water;provided that a pH of the oral liquid solution is 5.8 to 6.1 and theoral liquid solution is stable for at least 6 months when stored at atemperature ranging from 38° C. to 42° C. and not more than 25% relativehumidity; and provided that the valsartan or the pharmaceuticallyacceptable salt or solvate thereof is fully solubilized in the oralliquid solution.
 31. The method of claim 30, wherein the oral liquidsolution further comprises a sorbate salt.
 32. The method of claim 31,wherein the sorbate salt comprises potassium sorbate.
 33. The oralliquid solution of claim 1, wherein a mole ratio of citrate salt tovalsartan is about 3:1 to about 4:1.